Mitochondrial alterations near amyloid plaques in an Alzheimer’s disease mouse model
Open accessAbstract
While accumulation of amyloid-β (Aβ) deposited as senile plaques is a hallmark feature of Alzheimer's disease (AD), the neurotoxicity of these deposits remains controversial. Recent in vitro studies suggested a link between elevated Aβ and mitochondrial dysfunction that might contribute to the pathogenesis of AD. However, the in vivo evidence for mitochondria dysfunction caused by Aβ is still missing. Using intravital multiphoton imaging with a range of fluorescent markers, we systematically surveyed mitochondrial structural and functional changes in AD mouse models. We observed severe impairments to be limited to the vicinity of Aβ plaques, which included reduction of both numbers and membrane potential of mitochondria and the emergence of dystrophic and fragmented mitochondria. Both neuronal soma and neurites with oxidative stress show severe alterations in mitochondrial membrane potential in amyloid precursor protein mice. These results provide in vivo evidence revealing Aβ plaques as focal sources of toxicity that lead to severe structural and functional abnormalities in mitochondria. These alterations may contribute to neuronal network dysfunction and warrant further investigation as possible targets for therapeutic intervention in AD.
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TL;DR
Using intravital multiphoton imaging in APPswe:PSEN1dE9 mice, this study found that mitochondrial structural and functional abnormalities are largely restricted to the immediate vicinity of amyloid plaques. Mitochondria far from plaques appeared mostly normal, whereas near plaques there was mitochondrial loss, fragmentation/swelling, and reduced membrane potential.
Key findings
- Mitochondrial burden was significantly decreased within 16 µm of plaque borders compared with areas far from plaques (n = 13 plaques from 4 animals).
- Mitochondrial swelling was detected near 26 of 109 imaged/analyzed plaques from six animals, while cytosolic GFP-labeled neurites showed dystrophic morphology near all plaques (7 animals). Fragmented mitochondria occurred in 18 neurons from six Tg mice, with lengths of 2–4 µm; fragmented-mitochondria neurons were 38.4 ± 9.2 per mm³ in Tg mice versus 2.1 ± 1.4 per mm³ in Wt mice (n = 6 mice per genotype).
- Far from plaques (>50 µm), mitochondrial function did not differ significantly between Tg and Wt mice: JC-1 red/green ratio was 2.04 ± 0.16 in Wt versus 2.19 ± 0.15 in Tg (n = 12 imaging sites from 3 animals each), and MTR/MTG ratio was 4.03 ± 0.16 in Wt versus 4.35 ± 0.19 in Tg.
- Near plaques, MMP decreased over a ~20 µm radius: JC-1 ratio fell to 83% of the far-from-plaque value (n = 17 plaques from 5 animals); TMRE showed reduced signal near plaques (n = 46 plaques from 3 animals); MTR/MTG ratio decreased near plaques (n = 18 plaques from 4 animals). Dystrophic neurites had lower TMRE signal than normal neurites (0.38 ± 0.02, n = 80 vs 0.97 ± 0.01, n = 82; 5 animals), and oxidized neurons/neurites also showed reduced MMP (oxidized neurons 0.15 ± 0.03, n = 12 vs normal 0.97 ± 0.01, n = 93; oxidized neurites 0.38 ± 0.02, n = 80 vs normal 0.96 ± 0.01, n = 82; 3 animals). CAA did not reduce MMP in smooth muscle cells of leptomeningeal vessels (n ≥ 21 vessels from 5 mice).
Methods
- Intravital multiphoton imaging was performed in living APPswe:PSEN1dE9 transgenic mice (7–10 months old) and age-matched nontransgenic littermate controls, using cranial window implantation and methoxy-XO4 labeling of amyloid plaques.
- Mitochondria were labeled with viral mtGFP (lentivirus and AAV), AAV-GFP, AAV-roGFP, and mitochondrial dyes including MTR, MTG, TMRE, JC-1, DiOC6, and MitoFluo Red 589; FCCP was used to validate MMP-sensitive dyes, and COX IV immunostaining assessed mitochondrial loss.
- Image stacks were processed with ImageJ and IDL; plaque boundaries were defined at half-maximum methoxy-XO4 fluorescence, mitochondrial signal was measured in concentric bands (4 or 6 µm intervals), and data were reported as mean ± SE with t tests.
Limitations
- The paper states that the MTR/MTG ratio might be affected by differential diffusion/penetration rates of the two dyes in tissue, so caution is needed when imaging deep structures.
- The paper notes that lentivirus infects neurons and glial cells, so signal decreases near plaques might reflect mitochondrial loss in both cell types; AAV-mediated neuronal labeling was used to address this.
- Evident from the text: findings are from an AD mouse model and correlational in vivo imaging, not human AD tissue or causal manipulation; the study also does not establish the sequence linking calcium dysregulation, oxidative stress, and mitochondrial abnormalities, which the authors identify as important for future experiments.
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Claims the paper makes
0 of 15 cited sources checked · 0 supported · 0 flagged
- Findingown data
Cytosolic GFP-labeled neurites showed dramatic swelling/dystrophic morphology near all plaques.
“In contrast, cytosolic GFP-labeled neurites showed dramatic swelling/dystrophic morphology near all plaques, which is consistent with previous reports in AD mouse models (Tsai et al., 2004) and AD tissue (Cras et al., 1991; Fig. 1C, bottom, D; 7 animals).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Tsai et al., 2004
Not checked in the free run.
- cites Cras et al., 1991
Not checked in the free run.
- Findingown data
Mitochondrial swelling was detected near 26 plaques from six animals, out of 109 plaques imaged and analyzed.
“In total, we detected mitochondrial swelling near 26 plaques from six animals, out of a total of 109 plaques that were imaged and analyzed (Fig. 1D).”
Quote in the paperSubstantial claim - Findingown data
A similar mitochondrial loss near amyloid plaques was observed in Tg mice using AAV-mediated expression of cytosolic GFP and mtGFP.
“We observed a similar mitochondrial loss near amyloid plaques in Tg mice (data not shown) using this virus.”
Quote in the paperNot a substantial claim - Findingown data
No mtGFP signal was observed in the dense-core of A plaques.
“No mtGFP signal was observed in the dense-core of A plaques, consistent with our observations that neurites do not traverse through plaques (Spires et al., 2005).”
Quote in the paperSubstantial claim - Findingown data
A gross reduction of mtGFP signal was observed around methoxy-XO4-labeled plaques.
“However, a gross reduction of the mtGFP signal was observed around the methoxy-XO4-labeled plaques (Fig. 1B, top), suggesting that dense-core plaques caused a significant loss of mitochondria near the plaque borders.”
Quote in the paperSubstantial claim
- Findingown data
mtGFP expression revealed mitochondrial swelling in neurites in the immediate vicinity of a fraction of dense-core plaques.
“Furthermore, mtGFP expression revealed mitochondrial swelling in neurites (dendrites or axons) that was observed in the immediate vicinity of a fraction of dense-core plaques (Fig. 1C, top).”
Quote in the paperSubstantial claim - Findingown data
Mitochondrial burden within 16 μm from the boundary of plaques was significantly decreased compared with areas far from plaques (n = 13 plaques from 4 animals).
“The mitochondrial “burden” within the range of 16 m from the boundary of plaques was significantly decreased compared with that in the areas far from the plaques (n ϭ 13 plaques from 4 animals).”
Quote in the paperSubstantial claim - Findingown data
Mitochondrial morphology was affected in Tg mouse brain.
“In addition to the change in number, mitochondrial morphology was also affected in Tg mouse brain.”
Quote in the paperSubstantial claim - Findingown data
Remaining mitochondria near plaques were often fragmented and swollen.
“Remaining mitochondria near plaques were often fragmented and swollen.”
Quote in the paperSubstantial claim - Findingown data
The JC-1 fluorescence ratio (red/green) decreased from 2.48 ± 0.25 in untreated sites to 0.34 ± 0.08 in FCCP-treated sites (n ≥ 11 imaging sites from 2 animals, p < 0.001).
“Furthermore, the JC-1 fluorescence ratio (red/green) decreased from 2.48 Ϯ 0.25 in untreated sites to 0.34 Ϯ 0.08 in FCCP-treated sites (n Ն 11 imaging sites from 2 animals, p Ͻ 0.001).”
Quote in the paperSubstantial claim - Findingown data
Morphological alterations of mitochondria in neurons were seldom observed in age-matched Wt mice (2.1 ± 1.4 neurons per mm3) in contrast to Tg mice (38.4 ± 9.2 neurons per mm3).
“The morphological alterations of mitochondria in those neurons was seldom observed in neurons in agematched Wt mice 2.1 Ϯ 1.4 neurons per mm 3 brain volume, in contrast to 38.4 Ϯ 9.2 neurons per mm 3 in Tg mice (Fig. 2C; Wt, n ϭ 6 mice; Tg, n ϭ 6 mice).”
Quote in the paperSubstantial claim - Findingown data
There was a decrease in JC-1 ratio that extended to ~20 μm from the boundary of plaques (n=17 plaques from 5 animals).
“Consistent with the previous data, there was a decrease in ratio that extended to ϳ20 m from the boundary of plaques (Fig. 4A; n ϭ 17 plaques from 5 animals).”
Quote in the paperSubstantial claim - Findingown data
Both neuronal soma and neurites with oxidative stress show severe alterations in mitochondrial membrane potential in amyloid precursor protein mice.
“Both neuronal soma and neurites with oxidative stress show severe alterations in mitochondrial membrane potential in amyloid precursor protein mice.”
Quote in the paperSubstantial claim - Findingown data
Mitochondria within ~20 μm from plaques exhibited significant reductions in MMP.
“Moreover, mitochondria within ϳ20 m from plaques exhibited significant reductions in MMP, suggesting that amyloid plaques play a role as a source of toxicity that affects mitochondria function.”
Quote in the paperSubstantial claim - Findingown data
The range of decreased MMP revealed by TMRE extended to ~20 μm from the boundary of plaques (n=46 plaques from 3 animals).
“The range of decreased MMP revealed by TMRE also extended to ϳ20 m from the boundary of plaques (Fig. 4B; n ϭ 46 plaques from 3 animals).”
Quote in the paperSubstantial claim - Findingown data
The ratio of MTR/MTG was not changed in Tg mice compared with Wt controls in areas far from plaques (Wt = 4.03 ± 0.16; Tg = 4.35 ± 0.19).
“The ratio of MTR/MTG was not changed in Tg mice compared with Wt controls (Fig. 3D; Wt ϭ 4.03 Ϯ 0.16, n ϭ 60 imaging sites from 3 animals; Tg ϭ 4.35 Ϯ 0.19, n ϭ 65 imaging sites from 4 animals).”
Quote in the paperSubstantial claim - Findingown data
In wild-type mouse brain, mitochondrial cable-like structures in neurons were typically 2-30 μm long.
“In wild-type (Wt) mouse brain, the mitochondrial cable-like structures in neurons were typically 2-30 m long (Fig. 2B).”
Quote in the paperNot a substantial claim - Findingown data
Punctate TMRE staining was present in GFP-labeled dystrophic neurites near a subset of plaques.
“Punctate TMRE staining was present in GFPlabeled dystrophic neurites (Fig. 5 B, C) near a subset of plaques, suggesting that there are some functional mitochondria remaining in the dystrophic neurites.”
Quote in the paperSubstantial claim - Findingown data
Mitochondrial numbers were dramatically decreased in areas adjacent to A plaques.
“Together, we observed a dramatic decrease in mitochondrial numbers in areas adjacent to A plaques.”
Quote in the paperSubstantial claim - Findingown data
None of the tested dyes loaded brain following intravenous injection via tail vein.
“None of the tested dyes loaded brain with this approach (data not shown).”
Quote in the paperNot a substantial claim - Findingown data
No significant difference was observed in mitochondrial function between Wt and Tg mice in areas far from A plaques.
“Thus, no significant difference was observed in mitochondrial function between Wt and Tg mice.”
Quote in the paperSubstantial claim - Findingown data
Near plaques, there is a reduced density of mitochondria.
“Near plaques, there is a reduced density of mitochondria, abnormal morphology of mitochondria, and a loss of mitochondrial membrane potential in remaining mitochondria.”
- Also stated in: § Discussion · boosted
“There is a dramatic reduction in mitochondrial signal in the vicinity of dense-core plaques in APP/PS1 transgenic mice.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · boosted
- Findingown data
A small number of neurons close to plaques in Tg mice displayed fragmented mitochondria (18 neurons in six Tg mice).
“Surprisingly, in Tg mice, although the morphology of mitochondria in most of the neurons (Ͼ97% observed neurons in six Tg mice) appear to be normal, a small number of neurons close to plaques displayed fragmented mitochondria (18 neurons in six Tg mice; Fig. 2A, bottom).”
Quote in the paperSubstantial claim - Findingnone given
Detection of oxidized cell bodies is an extremely rare event.
“Detection of oxidized cell bodies is an extremely rare event.”
Quote in the paperNot a substantial claim - Findingown data
mtGFP-labeled mitochondria showed cable-like structures in living mouse brain.
“Similar to the observation in cultured neurons, mtGFP-labeled mitochondria showed cable-like structures in living mouse brain (Fig. 2A, top).”
Quote in the paperNot a substantial claim - Findingown data
In APP/PS1 transgenic mice, mitochondrial membrane potential indicated by TMRE staining is significantly decreased in oxidized neurons compared with normal neurons without oxidative stress.
“Compared with normal neurons without oxidative stress (Fig. 6A, yellow cells), MMP indicated by TMRE staining was significantly decreased in oxidized neurons (green cell, 0.15 Ϯ 0.03 in oxidized neurons, n ϭ 12, vs 0.97 Ϯ 0.01 in normal neurons, n ϭ 93; 3 animals; values are normalized fluorescent ratios of individual neurites vs average fluorescence intensity within each imaging plane; Fig. 6 A,”
Quote in the paperSubstantial claim - Findingown data
Similar decreases were observed with TMRE staining.
“Similar decreases were observed with TMRE staining, a commonly used dye that results in MMPsensitive loading of mitochondria (Fig. 4B), confirming a deficit in mitochondria function that is associated with plaques.”
Quote in the paperSubstantial claim - Findingown data
A decrease of COX subunit IV staining associated with plaques was observed.
“We consistently observed a decrease of COX subunit IV staining associated with plaques (Fig. 1E), which suggested the loss of intact mitochondria surrounding plaques.”
Quote in the paperSubstantial claim - Findingown data
Mitochondrial number was significantly decreased in areas immediately adjacent to plaques.
“Together, these data demonstrate that mitochondrial number was significantly decreased in the areas immediately adjacent to plaques.”
Quote in the paperSubstantial claim - Findingown data
TMRE intensity in dystrophic neurites was widely distributed, in contrast with normal neurites which showed a much tighter distribution.
“More detailed analysis showed that the TMRE intensity in dystrophic neurites was widely distributed, in contrast with those in normal neurites which showed a much tighter distribution.”
Quote in the paperSubstantial claim - Findingown data
The majority of mitochondria in the brains of mice with amyloid plaques appear structurally and functionally normal.
“We showed that the majority of mitochondria in the brains of mice with amyloid plaques appear structurally and functionally normal.”
Quote in the paperSubstantial claim - Findingown data
In APP/PS1 transgenic mice, mitochondrial membrane potential is significantly decreased in oxidized neurites compared with normal neurites.
“Severe alterations in MMP were also observed in oxidized neurites (0.38 Ϯ 0.02 in oxidized neurites, n ϭ 80, vs 0.96 Ϯ 0.01 in normal neurites, n ϭ 82; 3 animals; values are normalized fluorescent ratios of individual neurites vs average fluorescence intensity within each imaging plane; Fig. 6 B, C).”
Quote in the paperSubstantial claim - Findingown data
The ratio of MTR to MTG fluorescence was decreased from 4.05 ± 0.43 to 0.70 ± 0.16 in FCCP-treated side (n ≥ 8 imaging sites from 2 animals, p < 0.001).
“The ratio of MTR to MTG fluorescence was decreased from 4.05 Ϯ 0.43 to 0.70 Ϯ 0.16 (n Ն 8 imaging sites from 2 animals, p Ͻ 0.001; Fig. 3A).”
Quote in the paperSubstantial claim - Findingown data
Near plaques, there is abnormal morphology of mitochondria.
“Near plaques, there is a reduced density of mitochondria, abnormal morphology of mitochondria, and a loss of mitochondrial membrane potential in remaining mitochondria.”
- Also stated in: § Discussion · plain
“The bottom images show a neuron near plaques in a Tg mouse brain that shows severe fragmentation of mitochondria as a result of excessive mitochondrial fission.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
The average JC-1 fluorescent ratio (red/green) was significantly decreased to 83% of the value far from plaques in the area near plaques.
“In this area, the average JC-1 fluorescent ratio (red/green) was significantly decreased to 83% of the value far from plaques (Fig. 4A), indicating a reduction of MMP of individual mitochondria near plaques.”
Quote in the paperSubstantial claim - Findingown data
Severe alterations in mitochondrial structure and function were detected only in the proximity of dense core plaques.
“Severe alterations in mitochondria structure and function were, however, detected, but only in the proximity of dense core plaques.”
Quote in the paperSubstantial claim - Findingown data
No decrease in mitochondrial function (MMP) was detected in smooth muscle cells of leptomeningeal vessels near amyloid deposits, as indicated by TMRE staining.
“In contrast to the toxicity of amyloid deposits in neuronal tissues, we were unable to detect a decrease in mitochondrial function (MMP) in smooth muscle cells of leptomeningeal vessels near amyloid deposits, as indicated by TMRE staining (Fig. 4D).”
Quote in the paperSubstantial claim - Findingown data
In close proximity to senile plaques, decreased mitochondrial numbers stained with functional dyes were observed.
“In close proximity to senile plaques, we observed decreased mitochondrial numbers stained with the functional dyes, consistent with our previous results.”
Quote in the paperSubstantial claim - Findingown data
In Tg mice, morphology of mitochondria in most neurons (>97% observed neurons in six Tg mice) appeared normal.
“Surprisingly, in Tg mice, although the morphology of mitochondria in most of the neurons (Ͼ97% observed neurons in six Tg mice) appear to be normal, a small number of neurons close to plaques displayed fragmented mitochondria (18 neurons in six Tg mice; Fig. 2A, bottom).”
Quote in the paperSubstantial claim - Findingown data
The JC-1 red/green ratio was 2.04 ± 0.16 in Wt controls and 2.19 ± 0.15 in Tg mice in brain areas far from A plaques (>50 μm).
“The JC-1 red/green ratio was 2.04 Ϯ 0.16 (n ϭ 12 imaging sites from 3 animals) in Wt controls and 2.19 Ϯ 0.15 in Tg mice (n ϭ 12 imaging sites from 3 animals).”
Quote in the paperSubstantial claim - Findingown data
Oxidative stress was accompanied by mitochondrial dysfunction in living APP/PS1 transgenic mouse.
“Oxidative stress was accompanied by mitochondrial dysfunction in living APP/PS1 transgenic mouse.”
Quote in the paperSubstantial claim - Findingown data
The robust deficits occur within a halo that surrounds individual plaques, resulting in a ~20 μm radius of toxicity.
“The robust deficits occur within a halo that surrounds individual plaques, resulting in a ϳ20 m radius of toxicity.”
Quote in the paperSubstantial claim - Findingown data
These in vivo observations revealed mitochondrial impairments in AD mouse models.
“Together, these in vivo observations, for the first time, revealed mitochondrial impairments in AD mouse models.”
Quote in the paperSubstantial claim - Findingown data
Compared with normal neurites, TMRE fluorescence in dystrophic neurites is dramatically decreased and widely distributed.
“Summary data that indicate that compared with normal neurites, the TMRE fluorescence in the dystrophic neurites was dramatically decreased and widely distributed (n ϭ 5 animal, p Ͻ 0.001).”
Quote in the paperSubstantial claim - Findingown data
More dystrophic neurites than swollen mitochondria were observed near plaques in Tg mice.
“More dystrophic neurites than swollen mitochondria were observed near plaques in Tg mice.”
Quote in the paperNot a substantial claim - Findingown data
There is loss of COX IV surrounding plaques.
“Immunofluorescence of COX IV (red) showing loss of COX IV surrounding plaques.”
Quote in the paperSubstantial claim - Findingown data
CAA does not affect mitochondrial function in smooth muscle cells.
“CAA does not affect mitochondrial function in smooth muscle cells.”
Quote in the paperNot a substantial claim - Findingown data
Dystrophic neurites show severe alterations in mitochondrial membrane potential.
“Dystrophic neurites show severe alterations in MMP as shown in these representative images.”
Quote in the paperSubstantial claim - Findingown data
Both neuronal soma and neurites with oxidative stress show severe alterations in mitochondrial membrane potential.
“Both neuronal soma and neurites with oxidative stress show severe alterations in MMP as shown in these representative images.”
Quote in the paperSubstantial claim - Findingown data
Near plaques, there is a loss of mitochondrial membrane potential in remaining mitochondria.
“Near plaques, there is a reduced density of mitochondria, abnormal morphology of mitochondria, and a loss of mitochondrial membrane potential in remaining mitochondria.”
- Also stated in: § Discussion · plain
“The MMP-sensitive JC-1 ratio was decreased near plaques.”
- Also stated in: § Discussion · boosted
“A loss in membrane potential is confirmed using the fluorescent dye TMRE that shows a reduced signal near plaques in Tg mice.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
Mitochondrial membrane potential was not altered in areas far from amyloid plaques in the APP/PS1 transgenic mice.
“MMP was not altered in areas far from amyloid plaques in the APP/PS1 transgenic mice.”
- Also stated in: § Discussion · boosted
“No differences in the JC-1 ratio were observed in areas distant to A plaques (Ͼ50 m) in Tg mouse, compared with Wt mouse, demonstrating that most mitochondria have a normal resting membrane potential.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · boosted
- Premisecitation
Neurites do not traverse through plaques.
“No mtGFP signal was observed in the dense-core of A plaques, consistent with our observations that neurites do not traverse through plaques (Spires et al., 2005).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Spires et al., 2005
Not checked in the free run.
- Interpretationown data
Dense-core plaques caused a significant loss of mitochondria near the plaque borders.
“However, a gross reduction of the mtGFP signal was observed around the methoxy-XO4-labeled plaques (Fig. 1B, top), suggesting that dense-core plaques caused a significant loss of mitochondria near the plaque borders.”
Quote in the paperSubstantial claim - Interpretationown data
Soluble aggregates of A in Tg mice do not lead to appreciable changes in mitochondrial function and morphology in areas far from A plaques.
“Together, these results suggest that the soluble aggregates of A in the Tg mice do not lead to appreciable changes in mitochondrial function and morphology in areas far from A plaques.”
Quote in the paperSubstantial claim - Interpretationown data
Amyloid plaques play a role as a source of toxicity that affects mitochondrial function.
“Moreover, mitochondria within ϳ20 m from plaques exhibited significant reductions in MMP, suggesting that amyloid plaques play a role as a source of toxicity that affects mitochondria function.”
Quote in the paperSubstantial claim - Interpretationown data
A plaques are focal sources of toxicity that lead to severe structural and functional abnormalities in mitochondria.
“These results provide in vivo evidence revealing A plaques as focal sources of toxicity that lead to severe structural and functional abnormalities in mitochondria.”
Quote in the paperSubstantial claim - Study design and conductown data
Approaches for studying mitochondrial function in vivo via topical application of TMRE, DiOC6, JC-1, MTR, and MTG were validated.
“Thus, we validated approaches for studying mitochondrial function in vivo via topical application of TMRE, DiOC 6 , and JC-1, as well as MTR and MTG.”
Quote in the paperSubstantial claim - Interpretationown data
There are some functional mitochondria remaining in the dystrophic neurites.
“Punctate TMRE staining was present in GFPlabeled dystrophic neurites (Fig. 5 B, C) near a subset of plaques, suggesting that there are some functional mitochondria remaining in the dystrophic neurites.”
Quote in the paperNot a substantial claim - Interpretationown data
There is a larger variance in mitochondrial function and numbers in dystrophic neurites near plaques.
“Thus, there is a larger variance in mitochondrial function and numbers in dystrophic neurites near plaques (Fig. 5C).”
Quote in the paperSubstantial claim - Study design and conductown data
JC-1 staining in living mouse brain exhibited mitochondrial localization.
“JC-1 staining in living mouse brain exhibited mitochondrial localization as expected (Fig. 3B).”
Quote in the paperNot a substantial claim - Interpretationown data
The majority of mitochondria are not affected in Tg mice.
“These results are also consistent with the morphological studies with mtGFP virus labeling (Fig. 1) demonstrating that the majority of the mitochondria are not affected in the Tg mice.”
Quote in the paperSubstantial claim - Interpretationown data
The MMP in dystrophic neurites was reduced.
“This result demonstrates that the MMP in dystrophic neurites was reduced.”
Quote in the paperSubstantial claim - Interpretationown data
Mitochondrial function is severely impaired in the dystrophic neurites near amyloid plaques.
“These results demonstrate that mitochondrial function is severely impaired in the dystrophic neurites near amyloid plaques.”
Quote in the paperSubstantial claim - Premisenone given
Efforts to associate A toxicity with mitochondrial dysfunction are still limited to in vitro studies.
“However, the efforts to associate A toxicity with mitochondrial dysfunction are still limited to in vitro studies.”
Quote in the paperSubstantial claim - Interpretationown data
The reduction of MTR and MTG signals indicates loss of mitochondria in the immediate vicinity of plaques.
“We observed a significant reduction of both MTR signal and MTG signal, indicating loss of mitochondria in the immediate vicinity of plaques (Fig. 4C).”
Quote in the paperSubstantial claim - Interpretationown data
There is a reduction of MMP of individual mitochondria near plaques.
“In this area, the average JC-1 fluorescent ratio (red/green) was significantly decreased to 83% of the value far from plaques (Fig. 4A), indicating a reduction of MMP of individual mitochondria near plaques.”
Quote in the paperSubstantial claim - Interpretationown data
CAA does not have a direct effect on mitochondrial function in vessels with moderate vascular amyloid deposition.
“This observation suggests that CAA does not have a direct effect on mitochondrial function in vessels with moderate vascular amyloid deposition.”
Quote in the paperSubstantial claim - Interpretationown data
The decrease of COX IV staining suggests loss of intact mitochondria surrounding plaques.
“We consistently observed a decrease of COX subunit IV staining associated with plaques (Fig. 1E), which suggested the loss of intact mitochondria surrounding plaques.”
Quote in the paperSubstantial claim - Interpretationown data
A deficit in mitochondrial function is associated with plaques.
“Similar decreases were observed with TMRE staining, a commonly used dye that results in MMPsensitive loading of mitochondria (Fig. 4B), confirming a deficit in mitochondria function that is associated with plaques.”
Quote in the paperSubstantial claim - Study design and conductown data
AAV-mediated GFP expression in cortical neurons did not change the MMP indicated by TMRE staining (0.99 ± 0.02 in GFP-negative vs 0.95 ± 0.02 in GFP-positive; 3 animals).
“AAVmediated GFP expression in cortical neurons did not change the MMP indicated by TMRE staining (0.99 Ϯ 0.02 in GFP-negative neurons, n ϭ 23, vs 0.95 Ϯ 0.02 in GFP-positive neurons, n ϭ 26; 3 animals; values are normalized fluorescent ratios of individual neurites vs average fluorescence intensity within each imaging plane; Fig. 5A).”
Quote in the paperSubstantial claim - Study design and conductown data
The ratio of MTR and MTG fluorescence could be used as a ratiometric indicator of mitochondrial function.
“Moreover, the ratio of MTR and MTG fluorescence could be used as a ratiometric indicator of mitochondrial function.”
Quote in the paperSubstantial claim - Study design and conductown data
When applied directly to the neocortex of anesthetized mice, most of the dyes showed mitochondria-like localization.
“When applied directly to the neocortex of anesthetized mice, most of the dyes showed mitochondria-like localization (Figs.3A, MTG, MTR; B, JC-1, Fig. 4 B, TMRE).”
Quote in the paperSubstantial claim - Study design and conductown data
AAV-mediated GFP expression does not significantly change mitochondrial membrane potential.
“Right insert indicates that no significant change of MMP induced by AAV-mediated GFP expression (n ϭ 5 animal, p Ͻ 0.001).”
Quote in the paperSubstantial claim - Study design and conductown data
FCCP reduced the mitochondrial membrane potential in vivo as indicated with the MTR/MTG signal ratio in Wt mouse cortex.
“FCCP reduced the MMP in vivo as indicated with the MTR/MTG signal ratio in Wt mouse cortex.”
Quote in the paperSubstantial claim - Premisecitation
The roGFP probe can be used as an index of the redox status of cells.
“The probe is based on ratiometric imaging of fluorescence excited at 800 nm (oxidized) and 900 nm (reduced) and can be used as an index of the redox status of roGFP.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Dooley et al., 2004
Not checked in the free run.
- cites Cannon and Remington, 2008
Not checked in the free run.
- Interpretationown data
The results demonstrate a direct connection between mitochondrial dysfunction and amyloid plaques.
“Our results demonstrate a direct connection between mitochondrial dysfunction and amyloid plaques.”
Quote in the paperSubstantial claim - Interpretationreasoning
Calcium dyshomeostasis, oxidative stress, and mitochondrial dysfunction may be mechanistically linked.
“Indeed, our previous reports examining calcium dyshomeostasis and the current results that correlate oxidative stress with mitochondrial dysfunction suggest that these pathways may be mechanistically linked.”
Quote in the paperSubstantial claim - Premisecitation
The halo of deficits corresponds well with previous reports demonstrating local alterations in spine density, neuritic curvature, calcium dysregulation, and oxidative stress.
“This halo corresponds well with previous reports demonstrating local alterations in spine density, neuritic curvature, calcium dysregulation, and oxidative stress (Spires et al., 2005;Kuchibhotla et al., 2008;Meyer-Luehmann et al., 2008;Koffie et al., 2009;Xie et al., 2013).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Spires et al., 2005
Not checked in the free run.
- cites Kuchibhotla et al., 2008
Not checked in the free run.
- cites Meyer-Luehmann et al., 2008
Not checked in the free run.
- Study design and conductown data
FCCP reduced the mitochondrial membrane potential in vivo as indicated with the JC-1 ratio in Wt mouse cortex.
“FCCP reduced the MMP in vivo as indicated with the JC-1 ratio (red/green) in Wt mouse cortex.”
Quote in the paperNot a substantial claim
- May combine two claims. 14
- Classified as probably not a substantial claim. 9
- The quote only partly states this claim. 1
May combine two claims.
Findingown dataThere was a significant reduction of both MTR signal and MTG signal in the immediate vicinity of plaques.
“We observed a significant reduction of both MTR signal and MTG signal, indicating loss of mitochondria in the immediate vicinity of plaques (Fig. 4C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSevere mitochondrial impairments are limited to the vicinity of A plaques, including reduction of numbers and membrane potential and emergence of dystrophic and fragmented mitochondria.
“We observed severe impairments to be limited to the vicinity of A plaques, which included reduction of both numbers and membrane potential of mitochondria and the emergence of dystrophic and fragmented mitochondria.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataThe MitoFluo Red 589 signal was very weak and photobleached rapidly, and thus was not pursued further.
“Among the six dyes, the MitoFluo Red 589 signal was very weak and photobleached rapidly, and thus was not pursued further.”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Findingown dataThe lengths of fragmented mitochondria were distributed from 2 to 4 μm.
“The lengths of fragmented mitochondria were distributed from 2 to 4 m (Fig. 2B).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe ratio of MTR/MTG in remaining mitochondria decreased dramatically near plaques, with MMP decrease extending to ~20 μm from plaque border (n=18 plaques from 4 animals).
“Furthermore, the ratio of MTR/MTG in remaining mitochondria decreased dramatically near plaques.The MMP decrease extended to ϳ20 m from the border of plaques (Fig. 4C; n ϭ 18 plaques from 4 animals).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMTR fluorescence signal was reduced in the FCCP-treated side compared with the untreated side while MTG signal was unaffected.
“The fluorescence signal of MTR was reduced in the FCCP-treated side compared with the untreated side while the MTG signal was unaffected (Fig. 3A).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIn APPswe:PSEN1dE9 transgenic mice, A levels increase with age and A plaques are observed at approximately 4 months of age, accumulating progressively afterward.
“In the transgenic (Tg) mice (APPswe:PSEN1dE9), the levels of A increase with age and A plaques are observed at ϳ4 months of age, accumulating progressively afterward (Garcia-Alloza et al., 2006).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Garcia-Alloza et al., 2006
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe discrepancy between in vivo and in vitro results may be related to higher concentrations of synthetic Aβ used in vitro or to compensatory mechanisms in the intact brain.
“The discrepancy between these studies may be related to the much higher concentrations of synthetic A generally used in in vitro studies, or there exist compensatory mechanisms in the intact brain to accommodate diffuse low level neurotoxic insults.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIn vitro investigations have shown that exposure to Aβ causes mitochondrial dysfunction, including reduced membrane potential, increased permeability, increased ROS production, altered trafficking, and aberrant fission/fusion regulation.
“A variety of in vitro investigations have revealed that mitochondria have reduced membrane potential, increased permeability, increased ROS production, altered trafficking, and aberrant fission/fusion regulation when exposed to A (Keller et al., 1997;Mattson et al., 1998; Abramov et al., 2004;Lustbader et al., 2004;Manczak et al., 2006;Wang et al., 2008;Reddy, 2009;Calkins et al., 2011;Manczak et”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Keller et al., 1997 source
Not checked in the free run.
- cites Mattson et al., 1998
Not checked in the free run.
- cites Abramov et al., 2004
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataBoth TMRE and DiOC6 exhibited fluorescence changes in response to FCCP treatment in in situ assays.
“Using a similar approach, we also verified that both TMRE and DiOC 6 exhibited fluorescence changes in response to FCCP treatment (data not shown) in in situ assays.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisereasoningThe alterations in mitochondrial morphology and function in living animals remain to be elucidated.
“To consolidate the evidence for A-induced mitochondrial dysfunction in AD pathogenesis, the alterations in mitochondrial morphology and function in living animals remains to be elucidated.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIn previous work, oxidative stress near plaques was most dramatic in neurites, propagated to cell bodies, and preceded caspase activation leading to cell death within 24 h.
“By exploiting this reporter, we have previously determined that oxidative stress was most dramatic in neurites near plaques, propagated to cell bodies, and preceded activation of caspases that led to cell death within 24 h (Xie et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Xie et al., 2013
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationWhen tested in cultured CHO cells, all six mitochondrial dyes showed mitochondria-specific staining.
“When tested in cultured CHO cells, all dyes showed mitochondriaspecific staining (data not shown), as previously described”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenThe MTR/MTG ratio might be affected by differential diffusion/penetration rate of the two dyes in tissues, so caution must be used when imaging deep structures.
“However, it should be noted that the ratio might also be affected by a differential diffusion/penetration rate of the two dyes in tissues, so caution must be used when imaging deep structures.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThe majority of mitochondria in the brains of mice with amyloid plaques appearing normal is in stark contrast to numerous in vitro reports demonstrating more global disruption in response to exogenous Aβ.
“This surprising result is in stark contrast to the numerous reports using in vitro models that demonstrate more global disruption in response to exogenous A.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductcitationMTR can be used as a functional mitochondrial marker and MTG as a structural mitochondrial marker.
“Thus, consistent with previous reports in cultured cells and isolated mouse lens (Pendergrass et al., 2004), MTR can be used as a functional mitochondrial marker and MTG can be used as a structural mitochondrial marker.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Pendergrass et al., 2004
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCOX deficiency has been reported in dystrophic neurites of senile plaques.
“Deficiency of COX has been reported in dystrophic neurites of senile plaques (Pe ´rez-Gracia et al., 2008).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Pe ´rez-Gracia et al., 2008
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Interpretationnone givenAs the number of senile plaques increases with age, the amount and severity of neuropathological alterations will also increase, leading to progressive neural network dysfunction.
“Nonetheless, as the number of senile plaques increases with age, the amount and severity of neuropathological alterations will also increase, leading to progressive neural network dysfunction.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningThe reduction in mitochondrial membrane potential near plaques is a surrogate for impaired energy production by mitochondria, with profound implications for local metabolism and activity.
“This reduction in MMP is a surrogate to impaired energy production by mitochondria, which would have profound implications for local metabolism and activity.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The APPswe:PSEN1dE9 mouse model is a valid model for studying A plaque-associated mitochondrial alterations in Alzheimer's disease.
“Transgenic mice (7 to 10 months old) of either sex expressing mutant human APPswe/human PS1-⌬E9 were used along with age-matched nontransgenic littermate controls (Borchelt et al., 1997).”
The paper relies on this without support.
FCCP collapses mitochondrial membrane potential.
“To collapse the mitochondrial membrane potential, carbonyl cyanide 4-[trifluoromethoxy] phenylhydrazone (FCCP, 10 M; Sigma) was applied to the left hemisphere before MTR and MTG loading.”
The paper relies on this without support.
There is limited evidence examining the role of mitochondria in vivo, particularly in the presence of classical AD pathology such as senile plaques.
“While these results, as well as investigations in postmortem human tissue, have built a strong case for mitochondrial dysfunction in AD, there is limited evidence examining the role of mitochondria in vivo, particularly in the presence of classical AD pathology, e.g., senile plaques.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Excessive Ca2+ accumulation into mitochondria leads to decreased mitochondrial membrane potential and increased reactive oxygen species production in the APP/PS1 Alzheimer's disease mouse model.
“Excessive Ca2+ accumulation into mitochondria leads to decreased mitochondrial membrane potential and increased ROS production in the same AD mouse model [67,68,70].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [70]
Aβ can be toxic to neuronal mitochondria and causes Ca2+ elevation and changes in mitochondrial size and shape in the APP/PS1 Alzheimer's disease mouse model.
“Aβ can be toxic on neuronal mitochondria and causes Ca2+ elevation, changes in mitochondrial size and shape in APP/PS1 AD mouse model [70].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [70]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
GFP-expression comparison has conflicting animal counts
MinorThe Results describe this comparison as using 3 animals, while the Figure 5A caption reports 5 animals.
“AAVmediated GFP expression in cortical neurons did not change the MMP indicated by TMRE staining (0.99 Ϯ 0.02 in GFP-negative neurons, n ϭ 23, vs 0.95 Ϯ 0.02 in GFP-positive neurons, n ϭ 26; 3 animals;”
“Right insert indicates that no significant change of MMP induced by AAV-mediated GFP expression (n ϭ 5 animal, p Ͻ 0.001).”
Oxidized-neurite count differs between Results and Figure 6
MinorThe Results report 80 oxidized neurites for the MMP comparison, whereas the Figure 6C caption reports 8.
“0.38 Ϯ 0.02 in oxidized neurites, n ϭ 80, vs 0.96 Ϯ 0.01 in normal neurites, n ϭ 82; 3 animals;”
“n ϭ 8 oxidized neurites from 3 animals, p Ͻ 0.001”
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Mitochondria: Dynamic Organelles in Disease, Aging, and Development
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Mitochondrial abnormalities in Alzheimer's disease
Hirai, K., Aliev, G., Nunomura, A., Fujioka, H., Russell, R. L., Atwood, C. S., Johnson, A. B., Kress, Y., Vinters, H. V., Tabaton, M., et al. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-09-03017.2001 · Cited by 1,367 · cited 2× · see citing works
“, 2006) and altered mitochondrial structure has been observed (Hirai et al., 2001; Moreira et al., 2007).”
BackgroundABAD Directly Links Aß to Mitochondrial Toxicity in Alzheimer's Disease
Lustbader, J. W., Cirilli, M., Lin, C., Xu, H. W., Takuma, K., Wang, N., Caspersen, C., Chen, X., Pollak, S., Chaney, M., et al. (2004) · Science · doi:10.1126/science.1091230 · Cited by 1,303 · see citing works
Mitochondrial Membrane Potential Probes and the Proton Gradient: A Practical Usage Guide
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“Fluorescent probes for monitoring MMP have been frequently used for assessing mitochondrial function (Johnson et al., 1981; Perry et al., 2011; Nicholls, 2012).”
MethodManczak, M., Anekonda, T. S., Henson, E., Park, B. S., Quinn, J., & Reddy, P. H. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl066 · Cited by 1,104 · cited 3× · see citing works
“…increased ROS production, altered trafficking, and aberrant fission/fusion regulation when exposed to A (Keller et al., 1997; Mattson et al., 1998; Abramov et al., 2004; Lustbader et al., 2004; Manczak et al., 2006; Wang et al., 2008; Reddy, 2009; Calkins et al., 2011; Manczak et al., 2011).”
BackgroundMitochondria in neuroplasticity and neurological disorders
Mattson, M. P., Gleichmann, M., & Cheng, A. (2008) · Neuron · doi:10.1016/j.neuron.2008.10.010 · Cited by 1,081 · see citing works
Reers, M., Smith, T. W., & Chen, L. B. (1991) · Biochemistry · doi:10.1021/bi00232a015 · Cited by 1,052 · cited 1× · see citing works
“JC-1 is another vital functional mitochondrial dye used in vitro (Reers et al., 1991; Ankarcrona et al., 1995).”
BackgroundBorchelt, D. R., Ratovitski, T., van Lare, J., Lee, M. K., Gonzales, V., Jenkins, N. A., Copeland, N. G., Price, D. L., & Sisodia, S. S. (1997) · Neuron · doi:10.1016/s0896-6273(00)80974-5 · Cited by 1,023 · see citing works
Mitochondrial fragmentation in neurodegeneration.
Knott, A. B., Perkins, G., Schwarzenbacher, R., & Bossy-Wetzel, E. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2417 · Cited by 1,002 · cited 1× · see citing works
“Mitochondrial fusion and fission serves as a protective mechanism, disruption of which has been suggested to contribute to neurodegenerative disease (Chan, 2006; Knott et al., 2008; Wang et al., 2009).”
BackgroundRapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease
Meyer-Luehmann, M., Spires-Jones, T. L., Prada, C., Garcia-Alloza, M., de Calignon, A., Rozkalne, A., Koenigsknecht-Talboo, J., Holtzman, D. M., Bacskai, B. J., & Hyman, B. T. (2008) · Nature · doi:10.1038/nature06616 · Cited by 987 · cited 1× · see citing works
“This halo corresponds well with previous reports demonstrating local alterations in spine density, neuritic curvature, calcium dysregulation, and oxidative stress (Spires et al., 2005; Kuchibhotla et al., 2008; Meyer-Luehmann et al., 2008; Koffie et al., 2009; Xie et al., 2013).”
Self-citationMonitoring of relative mitochondrial membrane potential in living cells by fluorescence microscopy.
Johnson, L. V., Walsh, M. L., Bockus, B. J., & Chen, L. B. (1981) · The Journal of Cell Biology · doi:10.1083/jcb.88.3.526 · Cited by 914 · cited 1× · see citing works
“Fluorescent probes for monitoring MMP have been frequently used for assessing mitochondrial function (Johnson et al., 1981; Perry et al., 2011; Nicholls, 2012).”
MethodBrain glucose metabolism in the early and specific diagnosis of Alzheimer?s disease
Mosconi, L. (2005) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-005-1762-7 · Cited by 900 · cited 2× · see citing works
“For example, cerebral metabolism is reduced in affected brain regions (Mosconi, 2005; Gauthier et al., 2006) and altered mitochondrial structure has been observed (Hirai et al.”
BackgroundOxidative damage in Alzheimer's
Smith, M. A., Perry, G. L., Richey, P. L., Sayrec, L. M., Anderson, V. E., Beal, M. F., & Kowall, N. W. (1996) · Nature · doi:10.1038/382120b0 · Cited by 897 · cited 1× · see citing works
“Mitochondrial dysfunction is an attractive hypothesis for the pathogenesis of Alzheimer’s disease (AD) and aging-related senile dementia (Smith et al., 1996; Fukui and Moraes, 2008; Mattson et al., 2008).”
BackgroundKoffie, R. M., Meyer-Luehmann, M., Hashimoto, T., Adams, K. W., Mielke, M. L., Garcia-Alloza, M., Micheva, K. D., Smith, S. J., Kim, M. L., Lee, V. M., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0811698106 · Cited by 850 · cited 3× · see citing works
“…that a diffusible toxic molecule, e.g., oligomeric A , may be concentrated locally at dense core plaques, leading to these neurotoxic outcomes (Koffie et al., 2009); however, it is also possible that the outcomes are the result of indirect activity mediated, for example, by activated…”
BackgroundResultWang, X., Su, B., Siedlak, S. L., Moreira, P. I., Fujioka, H., Wang, Y., Casadesus, G., & Zhu, X. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0804871105 · Cited by 835 · cited 3× · see citing works
“…in mitochondrial membranes and interact with mitochondrial proteins, overproduction of which might affect dynamics of mitochondrial fusion/fission (Wang et al., 2008; Calkins et al., 2011; Manczak et al., 2011), impair mitochondrial transport, disrupt the electron transfer chain, increase ROS…”
BackgroundMańczak, M., Calkins, M. J., & Reddy, P. H. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr139 · Cited by 830 · cited 3× · see citing works
“…with mitochondrial proteins, overproduction of which might affect dynamics of mitochondrial fusion/fission (Wang et al., 2008; Calkins et al., 2011; Manczak et al., 2011), impair mitochondrial transport, disrupt the electron transfer chain, increase ROS production (Keller et al., 1997; Abramov et…”
BackgroundImaging Dynamic Redox Changes in Mammalian Cells with Green Fluorescent Protein Indicators
Dooley, C. T., Dore, T. M., Hanson, G. T., Jackson, W. C., Remington, S. J., & Tsien, R. Y. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312847200 · Cited by 776 · cited 1× · see citing works
“Redox-sensitive variants of the green fluorescent protein (roGFP) have been developed that allow the monitoring of oxidation/reduction potentials in cells using ratiometric methods (Dooley et al., 2004; Cannon and Remington, 2008).”
MethodCharacterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease
Garcia-Alloza, M., Robbins, E. M., Zhang-Nunes, S. X., Purcell, S. M., Betensky, R. A., Raju, S., Prada, C., Greenberg, S. M., Bacskai, B. J., & Frosch, M. P. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.08.017 · Cited by 744 · cited 1× · see citing works
“In the transgenic (Tg) mice (APPswe:PSEN1dE9), the levels of A increase with age and A plaques are observed at 4 months of age, accumulating progressively afterward (Garcia-Alloza et al., 2006).”
BackgroundSelf-citationCalkins, M. J., Manczak, M., Mao, P., Shirendeb, U., & Reddy, P. H. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr381 · Cited by 646 · cited 3× · see citing works
“…increased ROS production, altered trafficking, and aberrant fission/fusion regulation when exposed to A (Keller et al., 1997; Mattson et al., 1998; Abramov et al., 2004; Lustbader et al., 2004; Manczak et al., 2006; Wang et al., 2008; Reddy, 2009; Calkins et al., 2011; Manczak et al., 2011).”
BackgroundKuchibhotla, K. V., Goldman, S. T., Lattarulo, C. R., Wu, H.-Y., Hyman, B. T., & Bacskai, B. J. (2008) · Neuron · doi:10.1016/j.neuron.2008.06.008 · Cited by 614 · see citing works
Self-citationCytochrome oxidase deficiency in Alzheimer’s disease
Parker, W. D., Filley, C. M., & Parks, J. K. (1990) · Neurology · doi:10.1212/wnl.40.8.1302 · Cited by 598 · see citing works
Abramov, A. Y., Canevari, L., & Duchen, M. R. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.4042-03.2004 · Cited by 587 · cited 3× · see citing works
“…increased ROS production, altered trafficking, and aberrant fission/fusion regulation when exposed to A (Keller et al., 1997; Mattson et al., 1998; Abramov et al., 2004; Lustbader et al., 2004; Manczak et al., 2006; Wang et al., 2008; Reddy, 2009; Calkins et al., 2011; Manczak et al., 2011).”
BackgroundFibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches
Tsai, J., Grutzendler, J., Duff, K., & Gan, W.-B. (2004) · Nature Neuroscience · doi:10.1038/nn1335 · Cited by 561 · cited 2× · see citing works
“In contrast, cytosolic GFP-labeled neurites showed dramatic swelling/dystrophic morphology near all plaques, which is consistent with previous reports in AD mouse models (Tsai et al., 2004) and AD tissue (Cras et al., 1991; Fig.”
ResultSpires, T. L., Meyer-Luehmann, M., Stern, E. A., McLean, P. J., Skoch, J., Nguyen, P. T., Bacskai, B. J., & Hyman, B. T. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1879-05.2005 · Cited by 550 · cited 5× · see citing works
“…(Clontech) was inserted into the lentivirus vector CSCGW2 (a gift from Miguel Sena-Esteves; Sena-Esteves et al., 2004) and AAV vector pAAV-CBA– WPRE (Spires et al., 2005). roGFP was introduced into the construct pAAV-CBA-roGFP1-WPRE and the ratio of the emission fluorescence excited at 800 and 900…”
BackgroundMethodResultInfluentialSelf-citationPendergrass, W., Wolf, N. S., & Poot, M. J. M. (2004) · Cytometry Part A · doi:10.1002/cyto.a.20033 · Cited by 476 · see citing works
A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients
Maurer, I. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00112-3 · Cited by 475 · cited 1× · see citing works
“Mitochondrial enzymes important for metabolism, including cytochrome c oxidase (COX), -ketoglutarate dehydrogenase complex, and pyruvate dehydrogenase complex have been shown to be altered (Parker, et al., 1990; Gibson et al., 1998; Maurer et al., 2000).”
BackgroundKeller, J. N., Pang, Z., Geddes, J. W., Begley, J. G., Germeyer, A., Waeg, G., & Mattson, M. P. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.69010273.x · Cited by 439 · cited 3× · see citing works
“…2008; Calkins et al., 2011; Manczak et al., 2011), impair mitochondrial transport, disrupt the electron transfer chain, increase ROS production (Keller et al., 1997; Abramov et al., 2004; Manczak et al., 2006), and impair mitochondrial function (Mattson et al., 1998; Lustbader et al., 2004;…”
BackgroundReddy, P. H., Tripathi, R., Troung, Q., Tirumala, K., Reddy, T. P., Anekonda, V., Shirendeb, U. P., Calkins, M. J., Reddy, A. P., Mao, P., et al. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.10.011 · Cited by 394 · cited 1× · see citing works
“An effective treatment will likely include a combination of drugs that protect mitochondrial function (Calkins et al., 2012; Eckert et al., 2012; Reddy et al., 2012) and prevent amyloid accumulation.”
BackgroundAbnormalities of mitochondrial enzymes in Alzheimer disease
Gibson, G. E., Sheu, K.-F. R., & Blass, J. P. (1998) · Journal of Neural Transmission · doi:10.1007/s007020050099 · Cited by 345 · cited 1× · see citing works
“Mitochondrial enzymes important for metabolism, including cytochrome c oxidase (COX), -ketoglutarate dehydrogenase complex, and pyruvate dehydrogenase complex have been shown to be altered (Parker, et al., 1990; Gibson et al., 1998; Maurer et al., 2000).”
BackgroundSenile plaque neurites in Alzheimer disease accumulate amyloid precursor protein.
Cras, P. P., Kawai, M., Lowery, D. E., Gonzalez‐DeWhitt, P. A., Greenberg, B., & Perry, G. L. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.17.7552 · Cited by 314 · cited 1× · see citing works
“In contrast, cytosolic GFP-labeled neurites showed dramatic swelling/dystrophic morphology near all plaques, which is consistent with previous reports in AD mouse models (Tsai et al., 2004) and AD tissue (Cras et al., 1991; Fig.”
ResultOptimized large-scale production of high titer lentivirus vector pseudotypes
Sena‐Esteves, M., Tebbets, J. C., Steffens, S., Crombleholme, T. M., & Flake, A. W. (2004) · Journal of Virological Methods · doi:10.1016/j.jviromet.2004.08.017 · Cited by 287 · cited 3× · see citing works
“Mitochondrial-targeting GFP (mtGFP) was used to label mitochondria structurally. mtGFP from plasmid pAcGFP1-Mito (Clontech) was inserted into the lentivirus vector CSCGW2 (a gift from Miguel Sena-Esteves; Sena-Esteves et al., 2004) and AAV vector pAAV-CBA– WPRE (Spires et al., 2005). roGFP was introduced into the cons…”
MethodThe role of abnormal mitochondrial dynamics in the pathogenesis of Alzheimer’s disease
Wang, X., Su, B., Zheng, L., Perry, G. L., Smith, M. A., & Zhu, X. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.05867.x · Cited by 278 · cited 1× · see citing works
“Mitochondrial fusion and fission serves as a protective mechanism, disruption of which has been suggested to contribute to neurodegenerative disease (Chan, 2006; Knott et al., 2008; Wang et al., 2009).”
BackgroundAmyloid beta, mitochondrial structural and functional dynamics in Alzheimer's disease
Reddy, P. H. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.03.042 · Cited by 264 · cited 3× · see citing works
“…increased ROS production, altered trafficking, and aberrant fission/fusion regulation when exposed to A (Keller et al., 1997; Mattson et al., 1998; Abramov et al., 2004; Lustbader et al., 2004; Manczak et al., 2006; Wang et al., 2008; Reddy, 2009; Calkins et al., 2011; Manczak et al., 2011).”
BackgroundAmyloid β-peptide induces apoptosis-related events in synapses and dendrites
Mattson, M. P., Partin, J. V., & Begley, J. G. (1998) · Brain Research · doi:10.1016/s0006-8993(98)00763-x · Cited by 260 · cited 2× · see citing works
“…permeability, increased ROS production, altered trafficking, and aberrant fission/fusion regulation when exposed to A (Keller et al., 1997; Mattson et al., 1998; Abramov et al., 2004; Lustbader et al., 2004; Manczak et al., 2006; Wang et al., 2008; Reddy, 2009; Calkins et al., 2011;…”
BackgroundFukui, H., & Moraes, C. T. (2008) · Trends in Neurosciences · doi:10.1016/j.tins.2008.02.008 · Cited by 248 · see citing works
Rapid cell death is preceded by amyloid plaque-mediated oxidative stress
Xie, H., Hou, S., Jiang, J., Sekutowicz, M., Kelly, J., & Bacskai, B. J. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1217938110 · Cited by 172 · cited 7× · see citing works
“roGFP was introduced into the construct pAAV-CBA-roGFP1-WPRE and the ratio of the emission fluorescence excited at 800 and 900 nm was used as an index of the redox status of roGFP (Xie et al., 2013).”
BackgroundMethodInfluentialIncreased Autophagic Degradation of Mitochondria in Alzheimer Disease
Moreira, P. I., Siedlak, S. L., Wang, X., Santos, M. S., Oliveira, C. R., Tabaton, M., Nunomura, A., Szweda, L. I., Aliev, G. M., Smith, M. A., et al. (2007) · Autophagy · doi:10.4161/auto.4872 · Cited by 150 · cited 2× · see citing works
“, 2006) and altered mitochondrial structure has been observed (Hirai et al., 2001; Moreira et al., 2007).”
BackgroundMitochondrial Dysfunction—A Pharmacological Target in Alzheimer's Disease
Eckert, G. P., Renner, K., Eckert, S. H., Eckmann, J., Hagl, S., Abdel-Kader, R. M., Kurz, C., Leuner, K., & Muller, W. E. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8271-z · Cited by 126 · cited 1× · see citing works
“An effective treatment will likely include a combination of drugs that protect mitochondrial function (Calkins et al., 2012; Eckert et al., 2012; Reddy et al., 2012) and prevent amyloid accumulation.”
BackgroundKurt, M. A., Davies, D. C., Kidd, M., Duff, K., Rolph, S. C., JENNINGS, K. H., & Howlett, D. R. (2001) · Experimental Neurology · doi:10.1006/exnr.2001.7717 · Cited by 88 · cited 1× · see citing works
“These results suggest that few mitochondria are present or, if present, are fragmented in the majority of dystrophic neurites near plaques, and confirm previous ultrastructural determinations in APP/PS1 mice(Kurt et al., 2001; Dikranian et al., 2012).”
ResultFluorescence Measurement of Mitochondrial Membrane Potential Changes in Cultured Cells
Nicholls, D. G. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-382-0_8 · Cited by 73 · cited 1× · see citing works
“Fluorescent probes for monitoring MMP have been frequently used for assessing mitochondrial function (Johnson et al., 1981; Perry et al., 2011; Nicholls, 2012).”
MethodDystrophic neurites of senile plaques in Alzheimer’s disease are deficient in cytochrome c oxidase
Pérez-Gracia, E., Torrejón-Escribano, B., & Ferrer, I. (2008) · Acta Neuropathologica · doi:10.1007/s00401-008-0370-6 · Cited by 72 · cited 2× · see citing works
“Deficiency of COX has been reported in dystrophic neurites of senile plaques (Pérez-Gracia et al., 2008).”
BackgroundCalkins, M. J., Mańczak, M., & Reddy, P. (2012) · Pharmaceuticals · doi:10.3390/ph5101103 · Cited by 71 · see citing works
Cannon, M. B., & Remington, S. J. (2008) · Methods in molecular biology · doi:10.1007/978-1-59745-129-1_4 · Cited by 60 · cited 1× · see citing works
“Redox-sensitive variants of the green fluorescent protein (roGFP) have been developed that allow the monitoring of oxidation/reduction potentials in cells using ratiometric methods (Dooley et al., 2004; Cannon and Remington, 2008).”
MethodPositive effects of pollution?
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Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: Recent advances.
Wang, W., Zhao, F., Ma, X., Perry, G., & Zhu, X. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00376-6 · Cited by 1,274 · see citing works
Molecular mechanisms and consequences of mitochondrial permeability transition
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“Inhibition of caspase-3 activity is beneficial to reverse cognitive decline in APP mice possibly due to a requirement for caspase-3 activity in normal synaptic function [37, 38].”
Synaptic degeneration in Alzheimer disease
Tzioras, M., McGeachan, R. I., Durrant, C. S., & Spires-Jones, T. L. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-022-00749-z · Cited by 504 · see citing works
Amyloid toxicity in Alzheimer’s disease
Reiss, A. B., Arain, H. A., Stecker, M. M., Siegart, N. M., & Kasselman, L. J. (2018) · Reviews in the Neurosciences · doi:10.1515/revneuro-2017-0063 · Cited by 447 · see citing works
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“Furthermore, numerous studies have documented toxic effects such as mitochondrial loss [77], oxidative damage [78], synapse loss [29], and spine loss [75] in the immediate vicinity of plaques.”
VDAC1, mitochondrial dysfunction, and Alzheimer’s disease
Shoshan-Barmatz, V., Nahon-Crystal, E., Shteinfer-Kuzmine, A., & Gupta, R. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.03.010 · Cited by 286 · see citing works
Parkin-mediated mitophagy in mutant hAPP neurons and Alzheimer's disease patient brains
Ye, X., Sun, X., Starovoytov, V., & Cai, Q. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv056 · Cited by 274 · see citing works
“Reduction in Δψm and the emergence of dystrophic and fragmented mitochondria was shown to be limited to the vicinity of Aβ plaques in a live AD mouse model (39), suggesting a potential role of extracellular Aβ in mitochondrial alterations.”
BackgroundMitochondrial Aspects of Synaptic Dysfunction in Alzheimer’s Disease
Cai, Q., & Tammineni, P. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160726 · Cited by 274 · see citing works
“promote mitochondrial A accumulation and thus A -linked mitochondrial toxicity [121].”
Baek, S. H., Park, S. J., Jeong, J. I., Kim, S. H., Han, J., Kyung, J. W., Baik, S.-H., Choi, Y., Choi, B. Y., Park, J. S., et al. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.2385-16.2017 · Cited by 258 · see citing works
“In addition, mitochondrial abnormalities are found to arise before A plaque deposition (Xie et al., 2013a, 2013b).”
BackgroundMitophagy in Alzheimer’s Disease and Other Age-Related Neurodegenerative Diseases
Cai, Q., & Jeong, Y. Y. (2020) · Cells · doi:10.3390/cells9010150 · Cited by 263 · see citing works
Mitochondrial Dysfunction in Alzheimer’s Disease and the Rationale for Bioenergetics Based Therapies
Onyango, I. G., Dennis, J., & Khan, S. M. (2016) · Aging and Disease · doi:10.14336/ad.2015.1007 · Cited by 260 · see citing works
Alzheimer’s Disease: From Firing Instability to Homeostasis Network Collapse
Frère, S. G. A., & Slutsky, I. (2018) · Neuron · doi:10.1016/j.neuron.2017.11.028 · Cited by 230 · see citing works
Analyzing dendritic spine pathology in Alzheimer’s disease: Problems and opportunities
Dorostkar, M. M., Zou, C., Blazquez-Llorca, L., & Herms, J. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1449-5 · Cited by 235 · see citing works
“dynamics [38, 100] or mitochondrial integrity [216].”
Pera, M., Larrea, D., Guardia-Laguarta, C., Montesinos, J., Velasco, K., Agrawal, R., Xu, Y., Chan, R., Paolo, G. D., Mehler, M., et al. (2017) · EMBO Journal · doi:10.15252/embj.201796797 · Cited by 221 · see citing works
“Similarly, since C99 processing occurs at MAM, this could explain why A b has been found to colocalize with mitochondria (Hansson Petersen et al , 2008; Xie et al , 2013).”
A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease
Area-Gomez, E., de Groof, A., Bonilla, E., Montesinos, J., Tanji, K., Boldogh, I., Pon, L., & Schon, E. A. (2018) · Cell Death & Disease · doi:10.1038/s41419-017-0215-0 · Cited by 235 · see citing works
Oxidant/Antioxidant Imbalance in Alzheimer’s Disease: Therapeutic and Diagnostic Prospects
Wojsiat, J., Zoltowska, K. M., Laskowska-Kaszub, K., & Wojda, U. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/6435861 · Cited by 221 · see citing works
“Aβ may also increase the expression of heme oxygenase 1 (HO-1) enzyme which may secondarily compromise mitochondrial integrity [119], and Aβ plaques have been proposed to be a source of toxicity that induces severe mitochondrial structural and functional abnormalities in vivo in the mouse brain [120].”
BackgroundAlterations in Mitochondrial Quality Control in Alzheimer’s Disease
Cai, Q., & Tammineni, P. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00024 · Cited by 215 · see citing works
“One recent study provided in vivo evidence of the emergence of dystrophic and fragmented mitochondria and a reduction in the total number of mitochondria near amyloid plaques in living AD mouse brains (Xie et al., 2013).”
BackgroundInfluentialMitochondrial Dysfunction: Different Routes to Alzheimer’s Disease Therapy
Picone, P., Nuzzo, D., Caruana, L., Scafidi, V., & Carlo, M. D. (2014) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2014/780179 · Cited by 208 · see citing works
“Moreover, the mitochondrial membrane potential was 40% and 60% lower in 7WD4 and 7PA2 cells, respectively, compared to Chinese hamster ovary (CHO) controls.”
Fujita, Y., Taniguchi, Y., Shinkai, S., Tanaka, M., & Ito, M. (2016) · Geriatrics and gerontology international/Geriatrics & gerontology international · doi:10.1111/ggi.12724 · Cited by 199 · see citing works
Calcium Dyshomeostasis in Alzheimer’s Disease Pathogenesis
Cascella, R., & Cecchi, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094914 · Cited by 189 · see citing works
Inhibition of mitochondrial fragmentation protects against Alzheimer’s disease in rodent model
Wang, W., Yin, J., Ma, X., Zhao, F., Siedlak, S. L., Wang, Z., Torres, S., Fujioka, H., Xu, Y., Perry, G., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx299 · Cited by 175 · see citing works
“loid pathology (29) which implicated that mitochondrial dynamic changes are likely a late event secondary to the extensive amyloid pathology.”
Mańczak, M., Kandimalla, R. J. L., Fry, D., Sesaki, H., & Reddy, P. H. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw330 · Cited by 179 · see citing works
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Landel, V., Baranger, K., Virard, I., Loriod, B., Khrestchatisky, M., Rivera, S., Benech, P., & Féron, F. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-33 · Cited by 176 · see citing works
“Moreover, studies on different AD mouse models, including 5XFAD mice, reported increased levels of oxidative damage, which appear before A β deposition and therefore constitute an early event in disease pathogenesis [24,44,118,119].”
Mitochondrial quality control in human health and disease
Liu, B., Xu, C.-Z., Liu, Y., Lu, Z., Fu, T.-L., Li, G., Deng, Y., Luo, G., Ding, S. Z., Li, N., et al. (2024) · Military Medical Research · doi:10.1186/s40779-024-00536-5 · Cited by 189 · see citing works
The role of mitophagy in the regulation of mitochondrial energetic status in neurons
Han, S., Zhang, M., Jeong, Y. Y., Margolis, D. J., & Cai, Q. (2021) · Autophagy · doi:10.1080/15548627.2021.1907167 · Cited by 151 · see citing works
“We next assessed mitochondrial oxidation upon stimulation of energetic activity by utilizing Matrix-roGFP, ReductionOxidation-sensitive GFP (RoGFP) in the mitochondrial matrix [36,37].”
MethodMitochondrial Dysfunction Contributes to the Pathogenesis of Alzheimer’s Disease
Cabezas-Opazo, F., Vergara-Pulgar, K., Maria Jose Perez, J., Jara, C., Osorio‐Fuentealba, C., & Quintanilla, R. A. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2015/509654 · Cited by 148 · see citing works
Salehpour, F., Ahmadian, N., Rasta, S. H., Farhoudi, M., Karimi, P., & Sadigh‐Eteghad, S. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.06.025 · Cited by 141 · see citing works
“Previous studies in Alzheimer's disease (AD) had also shown the loss of brain mitochondrial number (Hirai et al., 2001; Xie et al., 2013).”
Mitophagy in neurological disorders
Zhang, L., Dai, L., & Li, D. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02334-5 · Cited by 141 · see citing works
Physiopathology of the Permeability Transition Pore: Molecular Mechanisms in Human Pathology
Bonora, M., Patergnani, S., Ramaccini, D., Morciano, G., Pedriali, G., Kahsay, A., Bouhamida, E., Giorgi, C., Wieckowski, M., & Pinton, P. (2020) · Biomolecules · doi:10.3390/biom10070998 · Cited by 135 · see citing works
“Consistent with this result, intravital multiphoton imaging of AD mouse models demonstrated that near senile Aβ plaques, mitochondria showed severe structural and functional abnormalities, suggesting that senile plaques are the main source of toxicity in vivo [112].”
ResultUnderwood, J., Robertson, K. R., & Winston, A. (2014) · AIDS · doi:10.1097/qad.0000000000000538 · Cited by 132 · see citing works
“ROS from mitochondrial dysfunction has also been shown to produce amyloid beta which itself causes mitochondrial dysfunction and ROS exacerbating the vicious cycle further [33,34].”
BackgroundMastroeni, D., Khdour, O. M., Delvaux, E., Nolz, J., Olsen, G., Berchtold, N. C., Cotman, C. W., Hecht, S. M., & Coleman, P. D. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.09.003 · Cited by 131 · see citing works
“In vitro [65], mouse model [6,7] and human studies [5] reveal that Ab and OAb are both toxic to mitochondria, suggesting that Ab may be responsible for the metabolic deficit observed in AD.”
BackgroundCorsetti, V., Florenzano, F., Atlante, A., Bobba, A., Ciotti, M. T., Natale, F., Della Valle, F., Borreca, A., Manca, A., Meli, G., et al. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv059 · Cited by 129 · see citing works
Subramanian, J., Savage, J. C., & Tremblay, M. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.592607 · Cited by 124 · see citing works
Yu, L., Wang, S., Chen, X., Yang, H., Li, X., Xu, Y., & Zhu, X. (2015) · Life Sciences · doi:10.1016/j.lfs.2014.11.021 · Cited by 127 · see citing works
“In the vicinity of Aβ, mitochondrial structural and functional impairments are observed, including membrane potential reduction and fusion/fission dynamics impairment [33,34].”
Plasma amyloid levels within the Alzheimer's process and correlations with central biomarkers
Hanon, O., Vidal, J., Lehmann, S., Bombois, S., Allinquant, B., Tréluyer, J., Gelé, P., Delmaire, C., Blanc, F., Mangin, J., et al. (2018) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2018.01.004 · Cited by 123 · see citing works
“The decrease of plasma amyloid level during the Alzheimer’s process could be explained by Ab clearance’s decrease from the brain (CSF) to the peripheral fluid (blood) because of alteration of blood-brain barrier permeability, glymphatic system, or vascular or microglial activation troubles [35,36].”
Yan, J., Liu, X.-H., Han, M., Wang, Y., Sun, X., Yu, N., Li, T., Su, B., & Chen, Z.-Y. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.08.005 · Cited by 123 · see citing works
Lee, A., Kondapalli, C., Virga, D. M., Lewis, T. L., Koo, S. Y., Ashok, A., Mairet‐Coello, G., Herzig, S., Foretz, M., Viollet, B., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-32130-5 · Cited by 113 · see citing works
Peng, Y., Gao, P., Shi, L., Chen, L., Liu, J., & Long, J. (2020) · Antioxidants & Redox Signaling · doi:10.1089/ars.2019.7763 · Cited by 110 · see citing works
“Decreases in respiratory capacity, increases in mitochondrial fragmentation, and fractures in the mitochondrial cristae structure occurs in the AD brain, and the abnormalities in mitochondria appear before pathological Ab plaque deposition (371, 438).”
BackgroundSalminen, A., Haapasalo, A., Kauppinen, A., Kaarniranta, K., Soininen, H. S., & Hiltunen, M. O. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.05.001 · Cited by 105 · see citing works
“Xie et al. (2013) observed in transgenic AD mice that mitochondria in the neurons close to b-amyloid plaques were gradually fragmented and showed a reduced expression of subunit 4 in the cytochrome c oxidase complex (complex IV).”
BackgroundZhang, X., Tian, Y., Yuan, P., Li, Y., Yaseen, M. A., Grutzendler, J., Moore, A. V., & Ran, C. (2014) · Chemical Communications · doi:10.1039/c4cc03731f · Cited by 106 · see citing works
Fossati, S., Giannoni, P., Solesio, M. E., Cocklin, S. L., Cabrera, E., Ghiso, J. A., & Rostagno, A. A. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.11.006 · Cited by 107 · see citing works
Calvo-Rodríguez, M., Hernando-Pérez, E., Núñez, L., & Villalobos, C. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00022 · Cited by 101 · see citing works
Mitophagy regulates integrity of mitochondria at synapses and is critical for synaptic maintenance
Han, S., Jeong, Y. Y., Sheshadri, P., Su, X. Y., & Cai, Q. (2020) · EMBO Reports · doi:10.15252/embr.201949801 · Cited by 92 · see citing works
“We assessed oxidatively stressed mitochondria in axons using Matrix-roGFP, RoGFP (reduction – oxidation-sensitive GFP) in mitochondrial matrix (Waypa et al , 2010; Xie et al , 2013).”
Zhao, F., Fang, F., Qiao, P., Yan, N., Gao, D., & Yan, Y. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/8360738 · Cited by 88 · see citing works
Calvo-Rodríguez, M., Kharitonova, E. K., Snyder, A. C., Hou, S. S., Sanchez-Mico, M. V., Das, S., Fan, Z., Shirani, H., Nilsson, K. P. R., Serrano‐Pozo, A., et al. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00702-2 · Cited by 97 · see citing works
“In line with these results, our group has previously shown structurally and functionally damaged mitochondria around Aβ plaques [32].”
BackgroundResultSelf-citationKukreja, L., Kujoth, G. C., Prolla, T. A., LEUVEN, F. V., & Vassar, R. J. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-16 · Cited by 86 · see citing works
“In an in vivo study, severe toxicity was induced in the immediate vicinity of amyloid plaques, causing structural and functional abnormalities in mitochondria [17].”
BackgroundZhang, W., Gu, G.-J., Shen, X., Zhang, Q., Wang, G., & Wang, P. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.10.040 · Cited by 84 · see citing works
“, 2007) may cause severe structural and functional abnormalities in mitochondria and contribute to neuronal network dysfunction in both transgenic mice overexpressing mutant amyloid precursor protein (APP) and in AD patients (Xie et al., 2013).”
BackgroundLaClair, K. D., Donde, A., Ling, J. P., Jeong, Y. H., Chhabra, R., Martin, L. J., & Wong, P. C. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1637-y · Cited by 81 · see citing works
“As noted above, though APPswe/PS1ΔE9 mice lack frank neuron loss, they exhibit significant synaptic and mitochondrial degeneration [12, 68], pathological features that are well suited to assess exacerbated neurodegeneration in an AD-related context.”
A mitochondrial delicacy: dynamin-related protein 1 and mitochondrial dynamics
Breitzig, M., Alleyn, M. D., Lockey, R. F., & Kolliputi, N. (2018) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00042.2018 · Cited by 81 · see citing works
“Mitochondrial fragmentation is also associated with enhanced amyloid- toxicity both in vitro and in vivo in Alzheimer’s disease (59, 61).”
BackgroundNeurotoxic β-amyloid oligomers cause mitochondrial dysfunction—the trigger for PANoptosis in neurons
Meng, X., Song, Q., Liu, Z., Liu, X., Wang, Y., & Liu, J. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1400544 · Cited by 78 · see citing works
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Self-citationOlesen, M. A., Villavicencio-Tejo, F., & Quintanilla, R. A. (2022) · Translational Neurodegeneration · doi:10.1186/s40035-022-00308-y · Cited by 71 · see citing works
Chen, Y., Zheng, H., Huang, X., Han, S., Zhang, D., Ni, J. Z., & He, X. (2015) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12473 · Cited by 69 · see citing works
In Vivo Imaging with Genetically Encoded Redox Biosensors
Kostyuk, A. I., Panova, A. S., Kokova, A. D., Kotova, D. A., Maltsev, D. I., Podgorny, O. V., Belousov, V. V., & Bilan, D. S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218164 · Cited by 63 · see citing works
“These observations indicate that oxidative stress accompanying Alzheimer’s disease may be linked, at least partially, with mitochondrial dysfunction [143].”
BackgroundImpact of Tau on Neurovascular Pathology in Alzheimer's Disease
Canepa, E., & Fossati, S. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2020.573324 · Cited by 65 · see citing works
In vivo functions of Drp1: Lessons learned from yeast genetics and mouse knockouts
Sesaki, H., Adachi, Y., Kageyama, Y., Itoh, K., & Iijima, M. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.11.024 · Cited by 61 · see citing works
“Similarly, fragmentation of mitochondria has been observed in mouse models for Alzheimer's disease which accumulate amyloid-β [63].”
BackgroundLi, X., & Jiang, L. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-0270-1 · Cited by 62 · see citing works
Pivotal role of nitrogen heterocycles in Alzheimer’s disease drug discovery
Kumari, S., Krishnaiah, M., Bachu, R. D., Boddu, S. H. S., Trippier, P. C., & Tiwari, A. K. (2022) · Drug Discovery Today · doi:10.1016/j.drudis.2022.07.007 · Cited by 60 · see citing works
Mitochondria and Alzheimer’s Disease: the Role of Mitochondrial Genetic Variation
Ridge, P. G., & Kauwe, J. S. K. (2018) · Current Genetic Medicine Reports · doi:10.1007/s40142-018-0132-2 · Cited by 57 · see citing works
Metabolic Disturbances in Diseases with Neurological Involvement
Duarte, J. M. N. (2014) · Aging and Disease · doi:10.14336/ad.2014.0500238 · Cited by 55 · see citing works
“…(which may include energy compounds, antioxidant therapy – particularly targeted to mitochondria – and modulators of mitochondrial dynamics), preventing or slowing the progression of neurodegeneration and improving the quality of life of the patients affected by these devastating illnesses.”
BackgroundHypoxia and GABA shunt activation in the pathogenesis of Alzheimer's disease
Salminen, A., Jouhten, P., Sarajärvi, T., Haapasalo, A., & Hiltunen, M. O. (2015) · Neurochemistry International · doi:10.1016/j.neuint.2015.11.005 · Cited by 54 · see citing works
Golgi Apparatus and Protein Trafficking in Alzheimer's Disease
Balogiannis, S. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-132660 · Cited by 52 · see citing works
“function [79], a fact which may further induce synaptic degeneration in AD [80], since many dendritic branches and abnormal spines were seen including unusual polymorphic mitochondria [23].”
Humpel, C. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00047 · Cited by 49 · see citing works
“The most robust deficits occur in this halo around the plaques within a radius of approximately 20µm, including local alterations in spine density, neuritic curvature, calcium dysregulation and oxidative stress (Xie et al., 2013).”
BackgroundJiang, L., Li, X., Mortadza, S. A. S., Lovatt, M., & Yang, W. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.07.002 · Cited by 53 · see citing works
Wang, H., Zhang, T., Ge, X., Chen, J., Zhao, Y., & Fu, J. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.117322 · Cited by 51 · see citing works
Environmental factors in the development and progression of late-onset Alzheimer’s disease
Wainaina, M. N., Chen, Z., & Zhong, C. (2014) · Neuroscience Bulletin · doi:10.1007/s12264-013-1425-9 · Cited by 51 · see citing works
“Other anesthetics, such as isofl urane([79]), isofl urane with hypoxia([80]), desfl urane with hypoxia([81]), and isofl urane with nitrous oxide([82]), also alter APP processing and subsequently increase Aβ production.”
BackgroundPresenilin 2-Dependent Maintenance of Mitochondrial Oxidative Capacity and Morphology
Contino, S., Porporato, P. E., Bird, M., Marinangeli, C., Opsomer, R., Sonveaux, P., Bontemps, F., Dewachter, I., Octave, J., Bertrand, L., et al. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00796 · Cited by 48 · see citing works
Brain Disorders and Chemical Pollutants: A Gap Junction Link?
Mesnil, M., Defamie, N., Naus, C. C. G., & Sarrouilhe, D. (2020) · Biomolecules · doi:10.3390/biom11010051 · Cited by 45 · see citing works
“This stress triggers nearby amyloid plaques and propagates into the cell body leading to caspase-dependent death in some vulnerable cortical neurons [511].”
BackgroundAβ25–35 Suppresses Mitochondrial Biogenesis in Primary Hippocampal Neurons
Dong, W., Wang, F., Guo, W.-Q., Zheng, X., Chen, Y., Zhang, W., & Shi, H. (2015) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-015-0222-6 · Cited by 44 · see citing works
Yu, Q., Du, F., Swerdlow, R. H., Yu, H., Chen, J. X., & Yan, S. S. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160532 · Cited by 42 · see citing works
“Abnormal mitochondrial morphology has also been reported in neurons from AD brains [11, 12].”
Broad activation of the Parkin pathway induces synaptic mitochondrial deficits in early tauopathy
Jeong, Y. Y., Han, S., Jia, N., Zhang, M., Sheshadri, P., Tammineni, P., Cheung, J., Nissenbaum, M., Baskar, S. S., Kwan, K. Y., et al. (2021) · Brain · doi:10.1093/brain/awab243 · Cited by 39 · see citing works
Nhu, N. T., Xiao, S., Liu, Y., Velmurugan, B. K., Cui, Z.-Y., & Lee, S. (2022) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2021.747901 · Cited by 42 · see citing works
Zhou, X., Tang, X., Li, T., Li, D., Gong, Z., Zhang, X., Li, Y., Zhu, J., Wang, Y., & Zhang, B. (2023) · Mediators of Inflammation · doi:10.1155/2023/6739691 · Cited by 41 · see citing works
Quintana, D. D., Garcia, J. A., Anantula, Y., Rellick, S. L., Engler-Chiurazzi, E. B., Sarkar, S. N., Brown, C. M., & Simpkins, J. W. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-190964 · Cited by 41 · see citing works
Mitochondrial chaperones in human health and disease
Bahr, T. A., Katuri, J., Liang, T. B., & Bai, Y. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.11.015 · Cited by 43 · see citing works
Amyloid-beta neuroprotection mediated by a targeted antioxidant
Giordano, C. R., Terlecky, L. J., Bollig-Fischer, A. B., Walton, P. A., & Terlecky, S. R. (2014) · Scientific Reports · doi:10.1038/srep04983 · Cited by 39 · see citing works
Chen, Y., Han, S., Huang, X., Ni, J., & He, X. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17020163 · Cited by 39 · see citing works
“Using in vivo live imaging analysis, severe mitochondrial impairments including the occurrence of mitochondrial fragmentation and decreases in the mitochondrial number and membrane potential were detected in the vicinity of Aβ plaque [5].”
BackgroundInsulin Resistance as a Common Link Between Current Alzheimer’s Disease Hypotheses
Alves, S. S., da Silva-Júnior, R. M. P., Servilha‐Menezes, G., Homolak, J., Šalković‐Petrišić, M., & Garcia‐Cairasco, N. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210234 · Cited by 38 · see citing works
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“Moreover, cytoplasmic plaque accumulation triggers the overproduction of intraneuronal ROS by disturbing mitochondrial activity (Xie et al., 2013).”
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BackgroundLoss of <i>Fis1</i> impairs proteostasis during skeletal muscle aging in <i>Drosophila</i>
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- Authors
- Xie, H., Guan, J., Borrelli, L. A., Xu, J., Serrano-Pozo, A., & Bacskai, B. J.
- Affiliations
- Massachusetts General Hospital (US)
- Tsinghua University (CN)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-10-23
- Volume
- 33
- Issue
- 43
- Pages
- 17042-17051
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3807029
- OpenAlex
- W2035815961
- Semantic Scholar
- 56c270d0938a0df939e932a219eaa2a69bb16728
- Cited by
- 185
- References
- 49
- Citations by year
- 2026: 10 · 2025: 8 · 2024: 11 · 2023: 12 · 2022: 18 · 2021: 23 · 2020: 14 · 2019: 8 · 2018: 19 · 2017: 9 · 2016: 18 · 2015: 16 · 2014: 17 · 2013: 2
- FWCI
- 12.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (2011Z02143, NCSF31100776)
- National Institute on Aging (AG024688, R01AG024688)
- National Institute of Biomedical Imaging and Bioengineering (EB 000768, R01EB000768)
- National Center for Research Resources (S10RR025645)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, amyloid plaques, mitochondrial dysfunction, mitochondrial membrane potential, mitochondrial fragmentation, oxidative stress, neurites, neurotoxicity
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Mice, Transgenic, Mitochondria, Neurites, Amyloid beta-Protein Precursor, Oxidative Stress, Mice, Membrane Potential, Mitochondrial, Plaque, Amyloid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
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