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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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55 Own result · 20 Own interpretation · 11 Own method · 9 Not checked yet · 3 No basis given
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In the paper
“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).”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
What the sources say
- Not checked yetcites Tsai et al., 2004
- Not checked yetcites Cras et al., 1991
plaincorrelationaln = 7- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
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“We observed a similar mitochondrial loss near amyloid plaques in Tg mice (data not shown) using this virus.”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
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“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.”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
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In the paper
“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).”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
plaincorrelationaln = 26- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
plaincorrelationaln = 13- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition to the change in number, mitochondrial morphology was also affected in Tg mouse brain.”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
plainn = 6- Asserted: passes — The authors put it forward as true.
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In the paper
“Remaining mitochondria near plaques were often fragmented and swollen.”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
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“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).”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
plaindirectn = 2- Asserted: passes — The authors put it forward as true.
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In the paper
“We observed a significant reduction of both MTR signal and MTG signal, indicating loss of mitochondria in the immediate vicinity of plaques (Fig. 4C).”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
hedgedcorrelationaln = 4- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Abstract
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“Among the six dyes, the MitoFluo Red 589 signal was very weak and photobleached rapidly, and thus was not pursued further.”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The lengths of fragmented mitochondria were distributed from 2 to 4 m (Fig. 2B).”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
plaincorrelationaln = 18- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
plaindirectn = 2- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
What the sources say
- Not checked yetcites Garcia-Alloza et al., 2006
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Discussion
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In the paper
“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”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Discussion
What the sources say
- Not checked yetcites Keller et al., 1997 source
- Not checked yetcites Mattson et al., 1998
- Not checked yetcites Abramov et al., 2004
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In the paper
“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.”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Introduction
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“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).”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
What the sources say
- Not checked yetcites Xie et al., 2013
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In the paper
“When tested in cultured CHO cells, all dyes showed mitochondriaspecific staining (data not shown), as previously described”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“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.”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Discussion
boosted- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
What the sources say
- Not checked yetcites Pendergrass et al., 2004
plainn = 2- Asserted: passes — The authors put it forward as true.
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In the paper
“Deficiency of COX has been reported in dystrophic neurites of senile plaques (Pe ´rez-Gracia et al., 2008).”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
What the sources say
- Not checked yetcites Pe ´rez-Gracia et al., 2008
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“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.”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
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In the paper
“This reduction in MMP is a surrogate to impaired energy production by mitochondria, which would have profound implications for local metabolism and activity.”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredIn the citing paper
“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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
“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;”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Discussion
“Right insert indicates that no significant change of MMP induced by AAV-mediated GFP expression (n ϭ 5 animal, p Ͻ 0.001).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Results
“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;”
§ Neurobiology of Disease Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model > Discussion
“n ϭ 8 oxidized neurites from 3 animals, p Ͻ 0.001”
Citations
Cites
Gauthier, S. G., Reisberg, ., Zaudig, M., Petersen, R. C., Ritchie, K. A., Broich, K., Belleville, S., Brodaty, H., Bennett, D. A., Chertkow, H. M., et al. (2006) · The Lancet · doi:10.1016/s0140-6736(06)68542-5 · Cited by 4,094
Mitochondria: Dynamic Organelles in Disease, Aging, and Development
Chan, D. C. (2006) · Cell · doi:10.1016/j.cell.2006.06.010 · Cited by 1,987
Ankarcrona, M., Dypbukt, J. M., Bonfoco, E., Zhivotovsky, B., Orrenius, S., Lipton, S. A., & Nicotera, P. (1995) · Neuron · doi:10.1016/0896-6273(95)90186-8 · Cited by 1,884
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×
“, 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
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×
“…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
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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
Amyloid toxicity in Alzheimer’s disease
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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
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
“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 281
“promote mitochondrial A accumulation and thus A -linked mitochondrial toxicity [121].”
Mitophagy in Alzheimer’s Disease and Other Age-Related Neurodegenerative Diseases
Cai, Q., & Jeong, Y. Y. (2020) · Cells · doi:10.3390/cells9010150 · Cited by 270
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“In addition, mitochondrial abnormalities are found to arise before A plaque deposition (Xie et al., 2013a, 2013b).”
BackgroundMitochondrial 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
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 242
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
“dynamics [38, 100] or mitochondrial integrity [216].”
Pera, M., Larrea, D., Guardia‐Laguarta, C., Montesinos, J., VELASCO, K. R., Agrawal, R. R., Xu, Y., Chan, R., Paolo, G. D., Mehler, M. F., et al. (2017) · The EMBO Journal · doi:10.15252/embj.201796797 · Cited by 236
“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
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
“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 226
“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 219
“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 206
Calcium Dyshomeostasis in Alzheimer’s Disease Pathogenesis
Cascella, R., & Cecchi, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094914 · Cited by 194
Inhibition of mitochondrial fragmentation protects against Alzheimer’s disease in rodent model
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“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 180
Buccellato, F. R., D’Anca, M., Fenoglio, C., Scarpini, E., & Galimberti, D. (2021) · Antioxidants · doi:10.3390/antiox10091353 · Cited by 179
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
“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 211
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
“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 155
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 142
“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 143
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
“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 136
“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 134
“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
Subramanian, J., Savage, J. C., & Tremblay, M. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.592607 · Cited by 127
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
“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
“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 126
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 119
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
“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 107
“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
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
Calvo-Rodríguez, M., Hernando-Pérez, E., Núñez, L., & Villalobos, C. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00022 · Cited by 103
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 96
“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 89
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 100
“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 85
“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 85
“, 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 76
“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
“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 84
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Chen, Y., Zheng, H., Huang, X., Han, S., Zhang, D., Ni, J., & He, X. (2015) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12473 · Cited by 69
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 66
“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 67
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 62
“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
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
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 59
Metabolic Disturbances in Diseases with Neurological Involvement
Duarte, J. M. N. (2014) · Aging and Disease · doi:10.14336/ad.2014.0500238 · Cited by 55
“…(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 56
Golgi Apparatus and Protein Trafficking in Alzheimer's Disease
Balogiannis, S. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-132660 · Cited by 53
“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 53
“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
Wang, H., Zhang, T., Ge, X., Chen, J., Zhao, Y., & Fu, J. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.117322 · Cited by 52
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 53
“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
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
“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 46
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
“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
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 46
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
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
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
Amyloid-beta neuroprotection mediated by a targeted antioxidant
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Metadata
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
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