Aerobic exercise improves astrocyte mitochondrial quality and transfer to neurons in a mouse model of Alzheimer's disease
Open accessAbstract
Mitochondrial dysfunction is a well‐established hallmark of Alzheimer's disease (AD). Despite recent documentation of transcellular mitochondrial transfer, its role in the pathogenesis of AD remains unclear. In this study, we report an impairment of mitochondrial quality within the astrocytes and neurons of adult 5 × FAD mice. Following treatment with mitochondria isolated from aged astrocytes induced by exposure to amyloid protein or extended cultivation, cultured neurons exhibited an excessive generation of reactive oxygen species and underwent neurite atrophy. Notably, aerobic exercise enhanced mitochondrial quality by upregulating CD38 within hippocampal astrocytes of 5 × FAD mice. Conversely, the knockdown of CD38 diminished astrocytic–neuronal mitochondrial transfer, thereby abolishing the ameliorative effects of aerobic exercise on neuronal oxidative stress, β‐amyloid plaque deposition, and cognitive dysfunction in 5 × FAD mice. These findings unveil an unexpected mechanism through which aerobic exercise facilitates the transference of healthy mitochondria from astrocytes to neurons, thus countering the AD‐like progression.
AI snapshot
Written from the paper’s full text.
TL;DR
In 5 × FAD mice, hippocampal astrocytic and neuronal mitochondria are damaged, and aged astrocyte-derived mitochondria can transfer to neurons and worsen oxidative stress and neurite atrophy. Aerobic exercise improves astrocytic mitochondrial quality and increases CD38-dependent astrocyte-to-neuron mitochondrial transfer, reducing AD-like pathology and cognitive impairment.
Key findings
- In 6-month-old 5 × FAD mice, more than 40% of mitochondria in hippocampal neuronal bodies, axon terminals, and astrocytes showed impaired ultrastructure, with decreased mitochondrial area and circumference; astrocytic mitochondrial quality and the number entering neurons were also reduced.
- In vitro, mitochondria from astrocytes exposed to 5 μM Aβ1–42 for 24 h or from 8-week cultured aged astrocytes entered neurons less efficiently and caused increased neuronal ROS, decreased ATP, reduced neurite branch number/length, and lower SYP and PSD-95.
- Four weeks of aerobic exercise improved mitochondrial quality in hippocampal astrocytes, increased astrocytic mitochondria entering neurons, reduced ROS and Aβ accumulation, and improved performance in the novel object recognition and Y-maze tests in 5 × FAD mice.
- CD38 knockdown reduced astrocytic–neuronal mitochondrial transfer and abolished the ameliorative effects of aerobic exercise on neuronal oxidative stress, β-amyloid plaque deposition, and cognitive dysfunction in 5 × FAD mice; aerobic exercise upregulated CD38 and CREB in the hippocampus.
Methods
- Five- and six-month-old male 5 × FAD mice and age-matched wild-type littermates received bilateral hippocampal injections of AAV-GFAP-mito-timer and/or CD38 siRNA, followed by 4 weeks of treadmill aerobic exercise.
- Primary astrocytes and neurons were cultured; astrocytes were treated with 5 μM Aβ1–42 oligomers for 24 h or repeatedly subcultured for 8 weeks to model aging, and astrocyte-derived mitochondria were isolated from conditioned medium and co-cultured with neurons.
- Analyses included transmission electron microscopy, immunofluorescence, Western blotting, ATP and ROS measurements, mitochondrial membrane potential, behavioral tests (novel object recognition and Y-maze), and ANOVA or t-tests as appropriate.
Limitations
- The paper states that future research is needed to determine whether aerobic exercise mediates mitochondria transfer from neurons to astrocytes, that the role of tunneling nanotubes in astrocyte-to-neuron mitochondrial transfer in AD remains undetermined, and that clinical studies are needed; it also notes a contrary view that age-related CD38 upregulation may itself cause mitochondrial dysfunction and that CD38–NAD+ interactions are complex.
- Evident from the Methods: all in vivo experiments used male mice only, so sex differences are not addressed; the findings are from a mouse model and in vitro cultures, not human tissue or clinical intervention.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
25 of 44 cited sources checked · 10 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Mitochondrial damage in astrocytes can lead to the accumulation of lipid droplets, thereby further exacerbating the pathological progression of Alzheimer's disease.
“Mitochondrial damage in astrocytes can lead to the accumulation of lipid droplets, thereby further exacerbating the pathological progression of AD [16, 17, 18].”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [16] Galea E, Weinstock LD, Larramona‐Arcas R, Pybus AF, Giménez‐Llort L, Escartin C, et al. Multi‐transcriptomic analysis points to early organelle dysfunction in human astrocytes in Alzheimer's disease. Neurobiol Dis. 2022; 166: 105655. 35143967 PMC9504227 source
The Discussion (Key implications and predictions; page unavailable) describes mitochondrial dysfunction in AD astrocytes. The Discussion’s model of astrocyte transformation predicts that this dysfunction contributes to AD progression, but neither passage links mitochondrial damage to lipid-droplet accumulation or identifies lipid droplets as a cause of worsening disease. Searches for lipid droplets and lipid accumulation found no such link in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [17] Mi Y, Qi G, Vitali F, Shang Y, Raikes AC, Wang T, et al. Loss of fatty acid degradation by astrocytic mitochondria triggers neuroinflammation and neurodegeneration. Nat Metab. 2023; 5: 445– 465. 36959514 PMC10202034 source
The Abstract reports that impaired astrocytic mitochondrial oxidative phosphorylation induces lipid-droplet accumulation followed by AD-like neurodegeneration. But the Discussion describes lipid-droplet formation as a protective response rather than a driver of reactivity or neuroinflammation. The paper therefore does not support the claim that the droplets themselves exacerbate AD progression. (LLM, conf=0.89)
Experimental — accuracy not yet measured - cites [18] Lee H, Cho S, Kim MJ, Park YJ, Cho E, Jo YS, et al. ApoE4‐dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes. Cell Rep. 2023; 42: 113183. 37777962 source
The Introduction and Discussion report dysfunctional mitochondria in ApoE4 human astrocytes and suggest that these changes contribute to AD pathogenesis. They do not report that mitochondrial damage causes lipid-droplet accumulation or that such droplets further exacerbate AD progression; the causal pathway studied instead runs from lysosomal cholesterol accumulation to impaired removal of damaged mitochondria. No page numbers are available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
Mitochondrial transfer between astrocytes and neurons represents a novel target for neuroprotection.
“A mounting body of evidence supports the notion that mitochondrial transfer between astrocytes and neurons represents a novel target for neuroprotection.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [13] Hayakawa K, Esposito E, Wang X, Terasaki Y, Liu Y, Xing C, et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016; 535: 551– 555. 27466127 PMC4968589 source
- cites [14] Ni XC, Wang HF, Cai YY, Yang D, Alolga RN, Liu B, et al. Ginsenoside Rb1 inhibits astrocyte activation and promotes transfer of astrocytic mitochondria to neurons against ischemic stroke. Redox Biol. 2022; 54: 102363. 35696763 PMC9198466
Not checked in the free run.
- Premisecitation
5×FAD mice exhibit abnormal neuron-astrocyte transmitophagy, characterized by increased degradation of neuronal mitochondria by astrocytes.
“Notably, 5 × FAD mice exhibit abnormal neuron–astrocyte transmitophagy, characterized by an increased degradation of neuronal mitochondria by astrocytes [15].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [15] Lampinen R, Belaya I, Saveleva L, Liddell JR, Rait D, Huuskonen MT, et al. Neuron‐astrocyte transmitophagy is altered in Alzheimer's disease. Neurobiol Dis. 2022; 170: 105753. 35569719 source
Results §3.1 (p. 5) report increased degradation of neuronal mitochondria by astrocytes harvested from 6- and 11-month-old 5xFAD mice in co-culture. The same passage reports no change in young astrocytes, so the unqualified claim about 5xFAD mice omits an important age restriction; the measured increase was in co-culture, not a quantified increase in intact mice. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
Mitochondrial intercellular transfer plays a crucial role in the maintenance of mitochondrial homeostasis.
“Recent evidence suggests that mitochondrial intercellular transfer also plays a crucial role in the maintenance of mitochondrial homeostasis [7, 8].”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [7] Liang W, Sagar S, Ravindran R, Najor RH, Quiles JM, Chi L, et al. Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired. Nat Commun. 2023; 14: 5031. 37596294 PMC10439183 source
The Results section reports that mitochondria released from adult mouse heart cells are taken up by macrophages and that this response is sufficient to maintain cardiac homeostasis during autophagy dysfunction. The Discussion describes this as an alternative quality-control pathway when lysosomal degradation is impaired. These passages support a role for intercellular mitochondrial transfer in homeostasis, but not the broader claim that it is generally crucial for maintaining mitochondrial homeostasis. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [8] Shanmughapriya S, Langford D, Natarajaseenivasan K. Inter and intracellular mitochondrial trafficking in health and disease. Ageing Res Rev. 2020; 62: 101128. 32712108 PMC7484258 source
- Premisecitation
The CD38 signaling pathway mediates the transfer of mitochondria from astrocytes to neurons.
“Recent studies have reported that the CD38 signaling pathway mediates the transfer of mitochondria from astrocytes to neurons [13].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [13] Hayakawa K, Esposito E, Wang X, Terasaki Y, Liu Y, Xing C, et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016; 535: 551– 555. 27466127 PMC4968589 source
- Findingown data
Western blot analysis reveals decreases in the expression levels of p62, PINK1, and LC3 in the hippocampus of 5×FAD mice that received exercise training.
“Western blot analysis further revealed decreases in the expression levels of p62, PINK1, and LC3, the markers of autophagic vacuoles [31], in the hippocampus of 5 × FAD mice that received exercise training (Figure S5A–D), further suggesting an improvement in mitochondrial quality.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [31] Mareninova OA, Jia W, Gretler SR, Holthaus CL, Thomas DDH, Pimienta M, et al. Transgenic expression of GFP‐LC3 perturbs autophagy in exocrine pancreas and acute pancreatitis responses in mice. Autophagy. 2020; 16: 2084– 2097. 31942816 PMC7595606 source
The Introduction (page unavailable) identifies LC3-II as localizing to autophagic vacuoles, and the Results describe SQSTM1/p62 colocalizing with LC3. The citation is attached to the description of these proteins as markers, not to the citing authors’ Western blot result (Figure S5); our copy does not establish PINK1 as a marker of autophagic vacuoles. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Findingown data
In hippocampal neurons and astrocytes of age-matched wild-type mice, the vast majority of mitochondria exhibit an intact ultrastructure.
“In contrast, in hippocampal neurons and astrocytes of age‐matched wild‐type (WT) mice, the vast majority of mitochondria exhibited an intact ultrastructure (Figure 1A).”
Quote in the paperSubstantial claim - Findingown data
Compared with wild-type mice, the quality and number of astrocytic mitochondria that enter adjacent neurons are reduced in 5×FAD mice.
“Furthermore, when compared with WT mice, the quality and number of astrocytic mitochondria that entered adjacent neurons were also reduced in 5 × FAD mice (Figure 1H–L).”
Quote in the paperSubstantial claim - Findingown data
Expression of superoxide dismutase 2 (SOD2) is decreased in hippocampal neurons and astrocytes of 5×FAD mice.
“Further analysis demonstrated that the expression of superoxide dismutase 2 (SOD2) decreased in hippocampal neurons and astrocytes of 5 × FAD mice (Figure S1C–F).”
Quote in the paperSubstantial claim - Findingown data
In 5×FAD mice, mitochondrial quality is markedly decreased in hippocampal astrocytes.
“The results showed that in 5 × FAD mice, the mitochondrial quality markedly decreased in hippocampal astrocytes (Figure 1E–G).”
Quote in the paperSubstantial claim - Findingown data
ROS levels are significantly elevated in the hippocampal neuron-enriched CA region in 5×FAD mice compared with wild-type littermates.
“Consistently, ROS levels were significantly elevated in the hippocampal neuron‐enriched CA region in 5 × FAD mice compared with the WT littermates (Figure S1A,B).”
Quote in the paperSubstantial claim - Findingown data
6-month-old 5×FAD mice have varying degrees of abnormalities in mitochondrial ultrastructure in hippocampal neuronal soma, axonal terminals, and astrocytes, manifested as condensed matrix, swollen cristae, and/or broken mitochondrial membrane.
“Transmission electron microscopy confirmed this view and revealed that 6‐month‐old 5 × FAD mice had varying degrees of abnormalities in the mitochondrial ultrastructure in hippocampal neuronal soma, axonal terminals, and astrocytes, manifested as condensed matrix, swollen cristae, and/or broken mitochondrial membrane (Figure 1A).”
Quote in the paperSubstantial claim - Findingown data
Aβ1-42-treated astrocytes have decreased ATP levels.
“Astrocytes exposed to Aβ1–42 resulted in decreased ATP levels (Figure 2N), further indicating their mitochondrial dysfunction.”
Quote in the paperSubstantial claim - Findingown data
The proportion and number of astrocyte-derived mitochondria entering cultured neurons are less in the Aβ1-42-treated group than in the control group.
“The proportion and number of astrocyte‐derived mitochondria entering cultured neurons in the Aβ1–42‐treated group were less than those in the control group (Figure 3E–G).”
Quote in the paperSubstantial claim - Findingown data
Transfer efficiency of aged astrocyte-derived mitochondria to neurons is reduced compared with mitochondria secreted by astrocytes cultured for 2 weeks.
“The transfer of aged astrocyte‐derived mitochondria to primary cultured neurons elevated neuronal ROS levels (Figure S4A,B), diminished ATP content (Figure S4C), and reduced neurite length and branching (Figure S4D–F), although transfer efficiency was reduced when compared with mitochondria secreted by astrocytes cultured for 2 weeks (Figure S4G,H).”
Quote in the paperNot a substantial claim - Findingown data
Hippocampal mitochondrial ROS levels increase in exercise-5×FAD mice after CD38 knockdown.
“We also found that hippocampal mitochondrial ROS levels and Aβ load increased in exercise‐5 × FAD mice after CD38 knockdown (Figure 6L–Q).”
Quote in the paperSubstantial claim - Findingown data
The quality of astrocytic mitochondria entering neurons is unchanged after CD38 knockdown.
“while the quality of astrocytic mitochondria entering neurons was unchanged (Figure 6F).”
Quote in the paperNot a substantial claim - Findingown data
Knockdown of CD38 expression inhibits astrocyte mitochondrial transport to neurons under physiological conditions in wild-type mice without aerobic exercise.
“Additionally, we injected con siRNA and CD38 siRNA into the hippocampus of WT mice without aerobic exercise, respectively, and found that knockdown of CD38 expression also inhibited astrocyte mitochondrial transport to neurons under physiological conditions (Figure S9A,B).”
Quote in the paperSubstantial claim - Findingown data
Cultured neurons incubated with mitochondria from Aβ1-42-exposed astrocytes exhibit decreases in the number and length of neurite branches.
“However, cultured neurons incubated with mitochondria from Aβ1–42 exposed astrocytes exhibited low ATP levels (Figure 3H), high ROS levels (Figure 3I,J), decreases in the number and length of neurite branches (Figure 3K–M), and low levels of synaptophysin (SYP) and post‐synaptic density protein 95 (PSD‐95) (Figure 3N–P), indicating the occurrence of atrophy and/or degeneration.”
Quote in the paperSubstantial claim - Findingown data
Aβ1-42-treated astrocytes have elevated expression levels of p16.
“In line with this, Western blot analysis revealed elevated expression levels of p16, a marker of cellular senescence [29], in astrocytes treated with Aβ1–42 (Figure 2C,D).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Zhao X, Lu J, Zhang C, Chen C, Zhang M, Zhang J, et al. Methamphetamine induces cardiomyopathy through GATA4/NF‐κB/SASP axis‐mediated cellular senescence. Toxicol Appl Pharmacol. 2023; 466: 116457. 36914120 source
- Findingown data
Mitochondrial quality is notably enhanced in hippocampal astrocytes, including those entering adjacent neurons, in 5×FAD mice with exercise training compared with their sedentary counterparts.
“The mitochondrial quality was notably enhanced in hippocampal astrocytes, including those entering adjacent neurons in 5 × FAD mice with exercise training, compared with their sedentary counterparts (Figure 4F–L).”
Quote in the paperSubstantial claim - Findingown data
The number of astrocytic mitochondria entering hippocampal neurons decreases after CD38 knockdown in both wild-type mice and 5×FAD mice that had undergone aerobic exercise.
“The results revealed a decrease in the number of astrocytic mitochondria entering hippocampal neurons after CD38 knockdown in both WT mice and 5 × FAD mice that had undergone aerobic exercise (Figure 6B–E)”
Quote in the paperSubstantial claim - Findingown data
Aerobic exercise increases SOD2 levels in neurons and astrocytes of 5×FAD mice.
“Additionally, aerobic exercise reduced ROS levels, increased SOD2 levels in neurons and astrocytes, and decreased Aβ accumulation of the hippocampus of 5 × FAD mice (Figure S6A–J).”
Quote in the paperNot a substantial claim - Findingown data
Cultured neurons incubated with mitochondria from Aβ1-42-exposed astrocytes exhibit high ROS levels.
“However, cultured neurons incubated with mitochondria from Aβ1–42 exposed astrocytes exhibited low ATP levels (Figure 3H), high ROS levels (Figure 3I,J), decreases in the number and length of neurite branches (Figure 3K–M), and low levels of synaptophysin (SYP) and post‐synaptic density protein 95 (PSD‐95) (Figure 3N–P), indicating the occurrence of atrophy and/or degeneration.”
Quote in the paperSubstantial claim - Findingown data
Astrocytes release mitochondria extracellularly, as detected by mitochondrial markers COX IV and TOM20 and ATP in culture medium.
“Furthermore, we demonstrated the extracellular release of mitochondria by astrocytes by successfully detecting the mitochondrial markers cytochrome c oxidase IV (COX IV) and translocase of outer mitochondrial membrane 20 (TOM20) and ATP levels in the culture medium (Figure 3A–C).”
Quote in the paperSubstantial claim - Findingown data
Aerobic exercise decreases Aβ accumulation in the hippocampus of 5×FAD mice.
“Additionally, aerobic exercise reduced ROS levels, increased SOD2 levels in neurons and astrocytes, and decreased Aβ accumulation of the hippocampus of 5 × FAD mice (Figure S6A–J).”
Quote in the paperSubstantial claim - Findingown data
Western blotting confirms the upregulation of CD38 expression and its transcriptional regulator CREB in the hippocampus of both mouse genotypes after aerobic exercise.
“Western blotting further confirmed the upregulation of CD38 expression and its transcriptional regulator CREB in the hippocampus of the both mouse genotypes after aerobic exercise (Figure 5C–E).”
Quote in the paperSubstantial claim - Findingown data
Cognitive function decreases in CD38-siRNA 5×FAD mice compared with NC-siRNA controls.
“The novel object recognition test and the Y‐maze test indicated a decrease in cognitive function in CD38‐siRNA 5 × FAD mice, compared with NC‐siRNA controls (Figure 6G–K).”
Quote in the paperSubstantial claim - Findingown data
The number of astrocytic mitochondria entering neurons is significantly reduced after CD38 knockdown.
“The results indicated a significant reduction in the number of astrocytic mitochondria entering neurons after CD38 knockdown (Figure S8D,E).”
Quote in the paperSubstantial claim - Findingown data
Most astrocytes undergo senescence after 8 weeks of culture with high expression levels of SA-β-gal and p16, compared with those cultured for 2 weeks.
“Most astrocytes underwent senescence after 8 weeks of culture with high expression levels of SA‐β‐gal and p16, compared with those cultured for 2 weeks (Figure S3A–D).”
Quote in the paperSubstantial claim - Findingown data
Aβ1-42-treated primary astrocytes exhibit a significantly higher percentage of SA-β-gal staining compared with untreated astrocytes.
“The Aβ‐treated primary astrocytes exhibited a significantly higher percentage of positive SA‐β‐gal staining, compared with untreated astrocytes (Figure 2A,B).”
Quote in the paperSubstantial claim - Findingown data
CD38 expression is decreased in cultured astrocytes after exposure to Aβ1-42 oligomers.
“We also observed decreases in CD38 expression in cultured astrocytes after exposure to Aβ1–42 oligomers (Figure S8F–I).”
Quote in the paperSubstantial claim - Findingown data
Cultured neurons incubated with mitochondria from Aβ1-42-exposed astrocytes exhibit low levels of synaptophysin (SYP) and post-synaptic density protein 95 (PSD-95).
“However, cultured neurons incubated with mitochondria from Aβ1–42 exposed astrocytes exhibited low ATP levels (Figure 3H), high ROS levels (Figure 3I,J), decreases in the number and length of neurite branches (Figure 3K–M), and low levels of synaptophysin (SYP) and post‐synaptic density protein 95 (PSD‐95) (Figure 3N–P), indicating the occurrence of atrophy and/or degeneration.”
Quote in the paperSubstantial claim - Findingown data
Release of mitochondria is reduced in cultured astrocytes after knockdown of CD38 expression.
“We found that the release of mitochondria was reduced in cultured astrocytes after knockdown of CD38 expression (Figure S8A–C).”
Quote in the paperSubstantial claim - Findingown data
CD38 expression in hippocampal astrocytes of 5×FAD mice is lower than in wild-type mice.
“Immunofluorescence results also demonstrated that the expression level of CD38 in hippocampal astrocytes of 5 × FAD mice was lower than in WT mice”
Quote in the paperSubstantial claim - Findingown data
Cultured neurons incubated with mitochondria from Aβ1-42-exposed astrocytes exhibit low ATP levels.
“However, cultured neurons incubated with mitochondria from Aβ1–42 exposed astrocytes exhibited low ATP levels (Figure 3H), high ROS levels (Figure 3I,J), decreases in the number and length of neurite branches (Figure 3K–M), and low levels of synaptophysin (SYP) and post‐synaptic density protein 95 (PSD‐95) (Figure 3N–P), indicating the occurrence of atrophy and/or degeneration.”
Quote in the paperSubstantial claim - Findingown data
Aerobic exercise reduces ROS levels in the hippocampus of 5×FAD mice.
“Additionally, aerobic exercise reduced ROS levels, increased SOD2 levels in neurons and astrocytes, and decreased Aβ accumulation of the hippocampus of 5 × FAD mice (Figure S6A–J).”
Quote in the paperSubstantial claim - Findingown data
Aerobic exercise upregulates CD38 expression in hippocampal astrocytes in both wild-type and Alzheimer's disease mice.
“and aerobic exercise upregulated CD38 expression in hippocampal astrocytes in both WT and AD mice (Figure 5A,B).”
Quote in the paperSubstantial claim - Findingown data
Aβ load increases in exercise-5×FAD mice after CD38 knockdown.
“We also found that hippocampal mitochondrial ROS levels and Aβ load increased in exercise‐5 × FAD mice after CD38 knockdown (Figure 6L–Q).”
Quote in the paperSubstantial claim - Interpretationown data
Mitochondrial oxidative damage occurs in hippocampal neurons and astrocytes under Alzheimer's disease-like pathological conditions.
“Together, these data confirm that mitochondrial oxidative damage occurs in hippocampal neurons and astrocytes under AD‐like pathological conditions.”
Quote in the paperSubstantial claim - Interpretationown data
Astrocytic mitochondria in Alzheimer's disease mice have impaired structure and function.
“These data together reveal impaired structure and function of astrocytic mitochondria in the AD mice.”
Quote in the paperSubstantial claim - Premisecitation
Mitochondrial dysfunction is a hallmark of Alzheimer's disease.
“Mitochondrial dysfunction is a well‐established hallmark of Alzheimer's disease (AD).”
- Also stated in: § DISCUSSION · plain
“Mitochondrial dysfunction represents a hallmark of aging and age‐related neurodegeneration, including AD [32].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [32] Müller WE, Eckert A, Kurz C, Eckert GP, Leuner K. Mitochondrial dysfunction: common final pathway in brain aging and Alzheimer's disease–therapeutic aspects. Mol Neurobiol. 2010; 41: 159– 171. Mitochondrial Dysfunction: Common Final Pathway in Brain Aging and Alzheimer's Disease—Therapeutic Aspects. 20461558 source
- Also stated in: § DISCUSSION · plain
- Premisecitation
CD38 serves as an ADP-ribose cyclase that produces cyclic ADP-ribose (cADPR), leading to the release of Ca2+.
“CD38 also serves as an ADP‐ribose cyclase that produces cyclic ADP‐ribose (cADPR), leading to the release of Ca2+.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [61] Wang Y, Ni J, Gao T, Gao C, Guo L, Yin X. Activation of astrocytic sigma‐1 receptor exerts antidepressant‐like effect via facilitating CD38‐driven mitochondria transfer. Glia. 2020; 68: 2415– 2426. 32460411 source
- Interpretationown data
Knocking down CD38 offsets the beneficial effect of aerobic exercise on Alzheimer's disease-like pathology.
“Knocking down CD38 offsets the beneficial effect of aerobic exercise on AD‐like pathology.”
Quote in the paperSubstantial claim - Interpretationreasoning
The transfer of mitochondria between neurons and astrocytes plays distinctive roles among different disease models.
“These findings indicate that the transfer of mitochondria between neurons and astrocytes plays distinctive roles among different disease models.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Aging astrocyte mitochondria that enter neurons might exacerbate oxidative damage to neurons.
“Aging astrocyte mitochondria that enter neurons might exacerbate oxidative damage to neurons.”
Quote in the paperNot a substantial claim - Interpretationown data
Inhibiting CD38 in the hippocampus hampers astrocytic mitochondrial transfer to neurons, thereby negating the ameliorating effect of aerobic exercise on oxidative stress and Aβ deposition in Alzheimer's disease mice.
“Inhibiting CD38 in the hippocampus hampers astrocytic mitochondrial transfer to neurons, thereby negating the ameliorating effect of aerobic exercise on oxidative stress and Aβ deposition in AD mice (Figure 7).”
Quote in the paperSubstantial claim - Interpretationcitation
Poor-quality mitochondria isolated from the supernatant of aged astrocytes induced by Aβ1-42 or long-term culture lead to neurite atrophy in cultured neurons.
“This conclusion is also supported by in vitro experiments demonstrating that poor‐quality mitochondria isolated from the supernatant of aged astrocytes induced by Aβ1–42 or long‐term culture lead to neurite atrophy in cultured neurons.”
Quote in the paperSubstantial claim - Interpretationreasoning
CD38-mediated mitochondrial transfer is a potential target for combating the occurrence of Alzheimer's disease.
“Taken together, both previous and current results emphasize CD38‐mediated mitochondrial transfer as a potential target for combating the occurrence of AD.”
Quote in the paperSubstantial claim - Interpretationown data
The CREB-CD38 signaling pathway appears to be a key regulatory factor for this intercellular mitochondrial transfer.
“The CREB‐CD38 signaling pathway appears to be a key regulatory factor for this intercellular mitochondrial transfer.”
Quote in the paperSubstantial claim - Interpretationown data
Transfer of mitochondria released by aged astrocytes to neurons results in oxidative damage.
“These in vitro data further underscored the transfer of mitochondria released by aged astrocytes to neurons, subsequently resulting in oxidative damage.”
Quote in the paperSubstantial claim - Interpretationown data
The beneficial effect of aerobic exercise on astrocyte-neuronal mitochondrial transfer depends on astrocyte CD38 expression.
“Moreover, this study suggests that the beneficial effect of aerobic exercise on astrocyte–neuronal mitochondrial transfer depends on astrocyte CD38 expression.”
Quote in the paperSubstantial claim - Interpretationreasoning
Merely improving transcellular transport, without enhancing mitochondrial quality, may be insufficient to combat Alzheimer's disease.
“Merely improving transcellular transport, without enhancing mitochondrial quality, may be insufficient to combat AD.”
Quote in the paperSubstantial claim - Premisecitation
Aerobic exercise enhances mitochondrial quality.
“It has been recently reported that aerobic exercise enhances mitochondrial quality [30].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [30] Memme JM, Erlich AT, Phukan G, Hood DA. Exercise and mitochondrial health. J Physiol. 2021; 599: 803– 817. 31674658 source
- Premisecitation
The CD38-cADPR-Ca2+ signaling pathway mediates the release of extracellular vesicles containing mitochondria from astrocytes, rescuing neurons from apoptosis after oxygen-glucose deprivation.
“Furthermore, the CD38‐cADPR‐Ca2+ signaling pathway mediates the release of extracellular vesicles containing mitochondria from astrocytes, rescuing neurons from apoptosis after oxygen–glucose deprivation [60].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [60] Park JH, Nakamura Y, Li W, Hamanaka G, Arai K, Lo EH, et al. Effects of O‐GlcNAcylation on functional mitochondrial transfer from astrocytes. J Cereb Blood Flow Metab. 2021; 41: 1523– 1535. 33153373 PMC8221762 source
- Classified as probably not a substantial claim. 19
- May combine two claims. 22
Classified as probably not a substantial claim.
PremisecitationImpaired brain energy metabolism is an early pathological manifestation of neurodegenerative diseases including Alzheimer's disease.
“Impaired brain energy metabolism serves as an early pathological manifestation of neurodegenerative diseases, including Alzheimer's disease (AD) [1, 2].”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [1] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large‐scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020; 26: 769– 780. 32284590 PMC7405761 source
The Results (Construction and Validation of a Consensus AD Protein Co-Expression Network; page not provided) report changes in mitochondrial and astrocyte/microglial metabolism protein modules during asymptomatic, preclinical AD. That supports early metabolism-related changes in AD, but not the stronger claim that brain energy metabolism is impaired. The comparison with other neurodegenerative diseases examines network changes in tissue from disease cases, not whether metabolic impairment is an early manifestation of those diseases. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [2] Han S, Zhang M, Jeong YY, Margolis DJ, Cai Q. The role of mitophagy in the regulation of mitochondrial energetic status in neurons. Autophagy. 2021; 17: 4182– 4201. 33757395 PMC8726713 source
The Introduction (page unavailable) says that AD patients show early metabolic deficits associated with impaired mitochondrial function, before histopathological or clinical abnormalities appear. The Discussion mentions other age-related neurodegenerative diseases but does not say that impaired energy metabolism is an early manifestation of those diseases generally. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationIn a mouse model of stroke, functional mitochondria can be transferred from astrocytes to adjacent neurons, mitigating neuronal damage.
“For instance, in a mouse model of stroke, functional mitochondria can be transferred from astrocytes to adjacent neurons, mitigating neuronal damage [13, 14].”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [13] Hayakawa K, Esposito E, Wang X, Terasaki Y, Liu Y, Xing C, et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016; 535: 551– 555. 27466127 PMC4968589 source
- cites [14] Ni XC, Wang HF, Cai YY, Yang D, Alolga RN, Liu B, et al. Ginsenoside Rb1 inhibits astrocyte activation and promotes transfer of astrocytic mitochondria to neurons against ischemic stroke. Redox Biol. 2022; 54: 102363. 35696763 PMC9198466 source
Checked before — its earlier verdict is held back until a new check runs.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationMitochondria are the primary producers of intracellular reactive oxygen species and are susceptible to oxidative stress caused by toxic metabolites such as β-amyloid.
“Mitochondria not only generate ATP but also act as the primary producers of intracellular reactive oxygen species (ROS) and are susceptible to oxidative stress caused by various toxic metabolites, such as β‐amyloid (Aβ) [3, 4].”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [3] Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell. 2012; 148: 1145– 1159. 22424226 PMC5381524 source
The section “Mitochondria Are Metabolic Signaling Centers” states that mitochondrial complexes I and III generate ROS, and the paper also describes mitochondrial ATP production. It does not establish that mitochondria are the primary intracellular ROS producers or say that β-amyloid causes oxidative stress in mitochondria; searches for amyloid and Alzheimer-related oxidative stress did not find that link. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [4] Yan SF, Akhter F, Sosunov AA, Yan SS. Identification and characterization of amyloid‐β accumulation in synaptic mitochondria. Methods Mol Biol. 2018; 1779: 415– 433. 29886547 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCD38 signaling is responsible for the extracellular release of mitochondria by astrocytes in a mouse model of stroke.
“Recent reports have unveiled that CD38 signaling is responsible for the extracellular release of mitochondria by astrocytes in a mouse model of stroke [13].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [13] Hayakawa K, Esposito E, Wang X, Terasaki Y, Liu Y, Xing C, et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016; 535: 551– 555. 27466127 PMC4968589 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAberrant mitochondrial exchange between cells is implicated in the pathogenesis of several neurological diseases including stroke and acute respiratory distress syndrome.
“The aberrant mitochondrial exchange between cells has been implicated in the pathogenesis of several neurological diseases including stroke and acute respiratory distress syndrome [9, 10, 11].”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [9] Liu D, Gao Y, Liu J, Huang Y, Yin J, Feng Y, et al. Intercellular mitochondrial transfer as a means of tissue revitalization. Signal Transduct Target Ther. 2021; 6: 65. 33589598 PMC7884415 source
The CNS section links intercellular mitochondrial transfer to stroke and discusses a possible role in Parkinson’s disease progression. But it describes transfer after stroke as aiding repair and recovery, not causing disease. The respiratory-system section discusses acute lung injury rather than acute respiratory distress syndrome, and likewise describes transfer as protective; it does not support the claim that aberrant exchange contributes to its pathogenesis. Page numbers were not available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [10] Masuzawa A, Black KM, Pacak CA, Ericsson M, Barnett RJ, Drumm C, et al. Transplantation of autologously derived mitochondria protects the heart from ischemia‐reperfusion injury. Am J Physiol Heart Circ Physiol. 2013; 304: H966– H982. 23355340 PMC3625892 source
- cites [11] Jackson MV, Morrison TJ, Doherty DF, McAuley DF, Matthay MA, Kissenpfennig A, et al. Mitochondrial transfer via tunneling nanotubes is an important mechanism by which mesenchymal stem cells enhance macrophage phagocytosis in the in vitro and in vivo models of ARDS. Stem Cells. 2016; 34: 2210– 2223. 27059413 PMC4982045 source
The Results and Conclusion (pages unavailable in our copy) link mitochondrial transfer to an ARDS-related infection model, but describe it as enhancing macrophage phagocytosis and antimicrobial activity—not as aberrant exchange contributing to disease pathogenesis. The paper does not address stroke or classify ARDS as a neurological disease. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationExercise promotes the upregulation of mitochondrial peroxisome proliferator-activated receptor gamma coactivator 1-alpha in muscle cells.
“Exercise promotes the upregulation of mitochondrial peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha, a principal regulator of mitochondrial biogenesis, within muscle cells [21].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [21] Ruas JL, White JP, Rao RR, Kleiner S, Brannan KT, Harrison BC, et al. A PGC‐1α isoform induced by resistance training regulates skeletal muscle hypertrophy. Cell. 2012; 151: 1319– 1331. 23217713 PMC3520615 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCD38 is highly enriched in astrocytes and regulates their development and activation.
“CD38 is highly enriched in astrocytes, which regulates their development and activation [13, 23].”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [13] Hayakawa K, Esposito E, Wang X, Terasaki Y, Liu Y, Xing C, et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016; 535: 551– 555. 27466127 PMC4968589 source
Extended Data Figure 5 reports that CD38 was primarily expressed in astrocytes in neuron–astrocyte co-cultures. The paper does not establish that CD38 regulates astrocyte development or activation; Extended Data Figure 8 reports no clear change in astrocyte morphology or GFAP expression after CD38 suppression. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [23] Hattori T, Kaji M, Ishii H, Jureepon R, Takarada‐Iemata M, Minh Ta H, et al. CD38 positively regulates postnatal development of astrocytes cell‐autonomously and oligodendrocytes non‐cell‐autonomously. Glia. 2017; 65: 974– 989. 28295574 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationOnly a minute fraction of mitochondria undergoes senescence under physiological conditions.
“Only a minute fraction of mitochondria undergoes senescence under physiological conditions [5].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [5] Miwa S, Kashyap S, Chini E, von Zglinicki T. Mitochondrial dysfunction in cell senescence and aging. J Clin Invest. 2022; 132: e158447. 35775483 PMC9246372 source
The Introduction section “What is mitochondrial dysfunction?” describes dysfunctional mitochondria accumulating in senescent cells, but does not say what fraction of mitochondria undergo senescence under physiological conditions. Searches for a minute or small fraction of senescent mitochondria and their prevalence under normal conditions found no passage addressing that claim; page numbers were unavailable. (LLM, conf=0.75)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationThe Y-maze test was conducted according to established laboratory protocols.
“The Y‐maze test was conducted as per the established laboratory protocols [72].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [72] Sarnyai Z, Sibille EL, Pavlides C, Fenster RJ, McEwen BS, Toth M. Impaired hippocampal‐dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin(1A) receptors. Proc Natl Acad Sci U S A. 2000; 97: 14731– 14736. 11121072 PMC18987 source
Probably not a substantial claim: may not pass S3 (load-bearing).
FindingcitationAfter repeated subculture for 8 weeks, astrocytes almost lost their proliferative ability, manifested as over 80% of cells expressing SA-β-Gal.
“Some astrocytes were repeatedly subcultured for 8 weeks to establish a replicated aging model. At this point, astrocytes almost lost their proliferative ability, manifested as over 80% of cells expressing SA‐β‐Gal [78, 79].”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [78] Bang M, Gonzales EL, Shin CY, Kwon KJ. Late passage cultivation induces aged astrocyte phenotypes in rat primary cultured cells. Biomol Ther (Seoul). 2021; 29: 144– 153. 33262320 PMC7921865 source
The Methods (Rat primary cortical astrocyte culture; page unavailable) describe repeated subculture to passage 7, and the Results (Late passage astrocytes show phenotypes of morphologically aged cells; page unavailable) report more SA-β-gal-positive cells than at passage 1. Our copy does not establish an eight-week duration, near-total loss of proliferative ability, or SA-β-gal positivity in over 80% of cells; it reports an approximately 1.3-fold increase instead. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [79] Bellaver B, Souza DG, Souza DO, Quincozes‐Santos A. Hippocampal astrocyte cultures from adult and aged rats reproduce changes in glial functionality observed in the aging brain. Mol Neurobiol. 2017; 54: 2969– 2985. 27026184 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMitoTimer is a mutant of the red fluorescent protein dsRed whose fluorescence shifts over time from green to red as the protein matures.
“AAV‐GFAP‐mito‐timer expressed a mutant of the red fluorescent protein, dsRed, in which fluorescence shifts over time from green to red as the protein matures [27].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [27] Hernandez G, Thornton C, Stotland A, Lui D, Sin J, Ramil J, et al. MitoTimer: a novel tool for monitoring mitochondrial turnover. Autophagy. 2013; 9: 1852– 1861. 24128932 PMC4028337 source
May combine two claims.
PremisecitationThe CD38-cADPR signaling pathway is involved in mitochondrial internalization, catalyzing the cyclization of extracellular NAD+ into intracellular cADPR, triggering the release of Ca2+, and promoting cytoskeleton remodeling, thus facilitating the internalization of extracellular mitochondria.
“Additionally, the CD38‐cADPR signaling pathway is involved in mitochondrial internalization, catalyzing the cyclization of extracellular nicotinamide adenine dinucleotide (NAD+) into intracellular cADPR, triggering the release of Ca2+, and promoting cytoskeleton remodeling, thus facilitating the internalization of extracellular mitochondria [62].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [62] Sun C, Liu X, Wang B, Wang Z, Liu Y, Di C, et al. Endocytosis‐mediated mitochondrial transplantation: transferring normal human astrocytic mitochondria into glioma cells rescues aerobic respiration and enhances radiosensitivity. Theranostics. 2019; 9: 3595– 3607. 31281500 PMC6587163 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationUnder transmission electron microscopy, synaptic terminals are spherical in shape and contain various synaptic vesicles.
“As for synaptic terminals, they are spherical in shape and contain various synaptic vesicles [75].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [75] Burette AC, Lesperance T, Crum J, Martone M, Volkmann N, Ellisman MH, et al. Electron tomographic analysis of synaptic ultrastructure. J Comp Neurol. 2012; 520(12): 2697– 2711. 22684938 PMC3856703 source
The Results section, “The presynaptic terminal” (page unavailable), describes vesicles within the terminal, supporting that part of the claim. The Discussion describes the vesicles as hollow spheres, but the copy does not say the terminal itself is spherical. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
Study design and conductcitationThe quantitative analysis of mitochondrial integrity was performed according to a previously described method.
“The quantitative analysis of mitochondrial integrity was performed according to the method previously described [76].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [76] Zhang KL, Li SJ, Pu XY, Wu FF, Liu H, Wang RQ, et al. Targeted up‐regulation of Drp1 in dorsal horn attenuates neuropathic pain hypersensitivity by increasing mitochondrial fission. Redox Biol. 2022; 49: 102216. 34954498 PMC8718665 source
May combine two claims.
Findingown dataIn neuronal bodies, axon terminals, and astrocytes of 5×FAD mice, more than 40% of mitochondrial ultrastructure is impaired, and mitochondrial area and circumference are decreased.
“Statistical results showed that in neuronal bodies, axon terminals, and astrocytes of AD mice, more than 40% of mitochondrial ultrastructure was impaired, and mitochondrial area and circumference were decreased (Figure 1B–D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTransfer of aged astrocyte-derived mitochondria to primary cultured neurons elevates neuronal ROS levels, diminishes ATP content, and reduces neurite length and branching.
“The transfer of aged astrocyte‐derived mitochondria to primary cultured neurons elevated neuronal ROS levels (Figure S4A,B), diminished ATP content (Figure S4C), and reduced neurite length and branching (Figure S4D–F), although transfer efficiency was reduced when compared with mitochondria secreted by astrocytes cultured for 2 weeks (Figure S4G,H).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAβ1-42-treated astrocytes have reductions in both the number and length of mitochondrial branches.
“Mitochondrial Mitotracker staining, combined with GFAP immunofluorescence, revealed reductions in both the number and length of mitochondrial branches in astrocytes exposed to Aβ1–42 (Figure 2E–G).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAβ1-42-treated astrocytes release fewer mitochondria and have lower mitochondrial SOD activity.
“We found that Aβ1–42‐treated astrocytes released fewer mitochondria and had lower mitochondrial SOD activity (Figure S2A–D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAerobic exercise enhances the cognitive performance of 5×FAD mice in both the novel object recognition test and the Y-maze test.
“Results from behavioral tests demonstrated that aerobic exercise enhanced the cognitive performance of 5 × FAD mice in both the novel object recognition test and the Y‐maze test (Figure S7A–C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAβ1-42-treated astrocytes have reduced mitochondrial membrane potential and increased mitochondrial ROS levels.
“The toxic impact of Aβ1–42 on cultured astrocytes was further confirmed by a reduction in mitochondrial membrane potential (Figure 2H,I) and an increase in mitochondrial ROS levels (Figure 2J–M).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMitochondria derived from aged astrocytes display abnormal morphology, decreased membrane potential, and increased ROS levels.
“Mitochondria derived from aged astrocytes displayed abnormal morphology (Figure S3E–G), decreased membrane potential (Figure S3H,I), and increased ROS levels (Figure S3J,K).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataExercised 5×FAD mice have a reduced proportion of damaged mitochondria in neurons and astrocytes, accompanied by increased mitochondrial area and circumference.
“Transmission electron microscopy showed that exercised 5 × FAD mice had a reduced proportion of damaged mitochondria in neurons and astrocytes, accompanied with increased mitochondrial area and circumference (Figure 4B–E).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAged mitochondria are sequestered within autophagosomes and transferred to lysosomes for degradation, while newly synthesized mitochondria are regenerated.
“The aged mitochondria are sequestered within autophagosomes and subsequently transferred to lysosomes for degradation, while newly synthesized mitochondria are promptly regenerated [6].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] Ashrafi G, Schwarz TL. The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. 2013; 20: 31– 42. 22743996 PMC3524633 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDuring exercise, CD38 in skeletal muscle is upregulated through the cAMP-responsive element-binding protein (CREB) pathway.
“During exercise, CD38 in skeletal muscle is upregulated through the cAMP‐responsive element‐binding protein (CREB) pathway [22].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Park DR, Nam TS, Kim YW, Lee SH, Kim UH. CD38‐cADPR‐SERCA signaling axis determines skeletal muscle contractile force in response to β‐adrenergic stimulation. Cell Physiol Biochem. 2018; 46: 2017– 2030. 29723871 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAerobic exercise is an effective measure for combating muscle aging by enhancing mitochondrial quality.
“Aerobic exercise has been demonstrated to be an effective measure for combating muscle aging by enhancing mitochondrial quality [20].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] Hood DA, Memme JM, Oliveira AN, Triolo M. Maintenance of skeletal muscle mitochondria in health, exercise, and aging. Annu Rev Physiol. 2019; 81: 19– 41. 30216742 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationExercise is one of the most pragmatic and secure strategies to mitigate the aging process and reduce the risk of Alzheimer's disease.
“Exercise emerges as one of the most pragmatic and secure strategies to mitigate the aging process and reduce the risk of AD [19].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] López‐Ortiz S, Valenzuela PL, Seisdedos MM, Morales JS, Vega T, Castillo‐García A, et al. Exercise interventions in Alzheimer's disease: a systematic review and meta‐analysis of randomized controlled trials. Ageing Res Rev. 2021; 72: 101479. 34601135 source
May combine two claims.
PremisecitationCD38 plays a crucial role in mediating mitochondrial release and enhances the expression of the O-GlcNA cycle.
“CD38 plays a crucial role in mediating mitochondrial release and also enhances the expression of the O‐GlcNA cycle [60].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [60] Park JH, Nakamura Y, Li W, Hamanaka G, Arai K, Lo EH, et al. Effects of O‐GlcNAcylation on functional mitochondrial transfer from astrocytes. J Cereb Blood Flow Metab. 2021; 41: 1523– 1535. 33153373 PMC8221762 source
May combine two claims.
Interpretationown dataAerobic exercise enhances mitochondrial quality and increases astrocytic-neuronal mitochondrial transfer by upregulating the CD38 signaling pathway.
“Aerobic exercise not only enhances mitochondrial quality, but also increases astrocytic–neuronal mitochondrial transfer by upregulating the CD38 signaling pathway.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationUnder transmission electron microscopy, the prominent feature of astrocyte cytoplasm is the presence of numerous parallel-arranged filamentous structures.
“The prominent feature of astrocyte cytoplasm is the presence of numerous parallel‐arranged filamentous structures [74].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [74] Karasek M, Swiltosławski J, Zielińiska A. Ultrastructure of the central nervous system: the basics. Folia Neuropathol. 2004; 42(Suppl B): 1– 9. 16903138
Not checked in the free run.
May combine two claims.
Interpretationown dataAstrocyte mitochondria with poor quality can be transferred to neurons in 5×FAD mice, potentially exacerbating oxidative damage to neurons and Aβ accumulation.
“We further found that astrocyte mitochondria with poor quality can be transferred to neurons in 5 × FAD mice, potentially exacerbating oxidative damage to neurons and Aβ accumulation.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataAerobic exercise promotes the entry of healthy mitochondria from astrocytes into neurons, potentially providing benefits in alleviating Alzheimer's disease-like pathology in 5×FAD mice.
“Collectively, these results suggest that aerobic exercise promotes the entry of healthy mitochondria from astrocytes into neurons, potentially providing benefits in alleviating AD‐like pathology in 5 × FAD mice.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe O-GlcNA cycle is involved in maintaining extracellular mitochondrial function during and after intercellular mitochondrial transfer.
“It has been reported that the O‐GlcNA cycle is involved in maintaining extracellular mitochondrial function during and after intercellular mitochondrial transfer [60].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [60] Park JH, Nakamura Y, Li W, Hamanaka G, Arai K, Lo EH, et al. Effects of O‐GlcNAcylation on functional mitochondrial transfer from astrocytes. J Cereb Blood Flow Metab. 2021; 41: 1523– 1535. 33153373 PMC8221762 source
May combine two claims.
Interpretationown dataAerobic exercise enhances mitochondrial quality in astrocytes of Alzheimer's disease mice and increases the efficiency of mitochondrial transfer from astrocytes to neurons, thus mitigating oxidative stress in neurons and reducing the deposition of Aβ plaques.
“In this study, we demonstrated that aerobic exercise enhances mitochondrial quality in astrocytes of AD mice and increases the efficiency of mitochondrial transfer from astrocytes to neurons, thus mitigating oxidative stress in neurons and reducing the deposition of Aβ plaques.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataAerobic exercise not only improves the mitochondrial quality of astrocytes but also facilitates astrocyte-neuron mitochondrial transfer, thereby ameliorating Alzheimer's disease-like pathology.
“In summary, the present study has revealed that aerobic exercise not only improves the mitochondrial quality of astrocytes but also facilitates astrocyte–neuron mitochondrial transfer, thereby ameliorating AD‐like pathology.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataAfter aerobic exercise, the low expression of CD38 in astrocytes of Alzheimer's disease mice is restored, and the ability of astrocytes to transfer healthy mitochondria to neurons is improved, thereby reducing neuronal oxidative stress and Aβ load.
“After aerobic exercise, the low expression of CD38 in astrocytes of AD mice was restored, and the ability of astrocytes to transfer healthy mitochondria to neurons was improved, thereby reducing neuronal oxidative stress and Aβ load.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationActivation of CD38 enhances mitochondrial release in astrocytes, while the use of an intracellular Ca2+ chelator or CD38 knockdown reduces mitochondrial release in astrocytes.
“Activation of CD38 enhances mitochondrial release in astrocytes, while the use of an intracellular Ca2+ chelator or CD38 knockdown reduces mitochondrial release in astrocytes [61].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [61] Wang Y, Ni J, Gao T, Gao C, Guo L, Yin X. Activation of astrocytic sigma‐1 receptor exerts antidepressant‐like effect via facilitating CD38‐driven mitochondria transfer. Glia. 2020; 68: 2415– 2426. 32460411 source
The paper relies on this without support.
The 5×FAD mouse model recapitulates key aspects of Alzheimer's disease relevant to mitochondrial dysfunction and the effects of aerobic exercise.
“Five‐ and six‐month‐old male 5 × FAD mice and age‐matched WT littermate mice with a C57BL/6 background were utilized for this study.”
The paper relies on this without support.
Aβ1–42 oligomer treatment of primary astrocytes is a valid model of astrocyte aging in Alzheimer's disease.
“Primary astrocytes were isolated from the hippocampus of newborn mice and cultured for 2 weeks before treatment with 5 μM Aβ1–42 oligomers for 24 h.”
The paper relies on this without support.
CD38 siRNA specifically reduces CD38 expression without off-target effects on mitochondrial transfer.
“In order to validate this notion, we downregulated CD38 gene expression in primary astrocytes using CD38 short interfering RNA (siRNA).”
The paper relies on this without support.
Under transmission electron microscopy, neuronal nuclei have low chromatin electron density with a small amount of heterochromatin plaques.
“Under transmission electron microscopy, the chromatin electron density of neuronal nuclei is low with a small amount of heterochromatin plaques.”
The paper relies on this without support.
Under transmission electron microscopy, neuronal cytoplasm has very low electron density and is rich in plate-like rough endoplasmic reticulum.
“The cytoplasmic electron density of neurons is also very low and rich in plate‐like rough endoplasmic reticulum.”
The paper relies on this without support.
Under transmission electron microscopy, the nucleus of astrocytes is usually irregular in shape with heterochromatin accumulation near the nuclear membrane region.
“The nucleus of astrocytes is usually irregular in shape with heterochromatin accumulation near the nuclear membrane region.”
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.
Primary astrocyte tissue source differs between Results and Methods
MajorThe Results say the primary astrocytes were isolated from newborn hippocampus, whereas the culture method says they were established from neonatal cerebral cortices.
“Primary astrocytes were isolated from the hippocampus of newborn mice and cultured for 2 weeks before treatment with 5 μM Aβ1–42 oligomers for 24 h.”
“Primary astrocyte cultures were established using cerebral cortices from neonatal mice [77].”
The same GFAP antibody is identified as both mouse and rat
MinorThe SA-β-gal/GFAP staining method calls antibody ab279291 a mouse anti-GFAP antibody, but the immunofluorescence method calls that same antibody a rat monoclonal anti-GFAP antibody.
“They were then incubated with a mouse anti‐GFAP antibody (ab279291, 1:500, Abcam) at 4°C overnight.”
“To label astrocytes, sections and coverslips were incubated with rat monoclonal anti‐GFAP (ab279291, 1:500, Abcam).”
Figure 6 mice have inconsistent reported ages
MinorThe methods described for this experiment start with 6-month-old mice and add four weeks of exercise, which would make them about 7 months old. The Figure 6 caption instead calls them 6.5 months old.
“we injected CD38 siRNA into the bilateral hippocampus of 6‐month‐old WT and 5 × FAD mice that had previously received an injection of AAV‐GFAP‐mito‐timer virus. These animals were then subjected to 4 weeks of aerobic exercise training”
“FIGURE 6 Inhibition of astrocytic mitochondrial entry into neurons and aggravation of Alzheimer's disease (AD)‐like phenotype in 6.5‐month‐old 5 × FAD mice receiving aerobic exercise after CD38 knockdown.”
Cites
Neurotoxic reactive astrocytes are induced by activated microglia
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S., Peterson, T. C., et al. (2017) · Nature · doi:10.1038/nature21029 · Cited by 7,971 · see citing works
Mitochondria: In Sickness and in Health
Nunnari, J., & Suomalainen, A. (2012) · Cell · doi:10.1016/j.cell.2012.02.035 · Cited by 3,479 · see citing works
Oxidative stress and the amyloid beta peptide in Alzheimer’s disease
Cheignon, C., Tomas, M., Bonnefont-Rousselot, D., Faller, P., Hureau, C., & Collin, F. (2018) · Redox Biology · doi:10.1016/j.redox.2017.10.014 · Cited by 2,185 · see citing works
The pathways of mitophagy for quality control and clearance of mitochondria
Ashrafi, G., & Schwarz, T. L. (2013) · Cell Death & Differentiation · doi:10.1038/cdd.2012.81 · Cited by 1,900 · see citing works
Fang, E. F., Hou, Y., Palikaras, K., Adriaanse, B. A., Kerr, J. S., Yang, B., Lautrup, S., Hasan-Olive, M. M., Caponio, D., Dan, X., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0332-9 · Cited by 1,740 · see citing works
Transfer of mitochondria from astrocytes to neurons after stroke
Hayakawa, K., Esposito, E., Wang, X., Terasaki, Y., Liu, Y., Xing, C., Ji, X., & Lo, E. H. (2016) · Nature · doi:10.1038/nature18928 · Cited by 1,423 · see citing works
Object recognition test in mice
Leger, M., Quiedeville, A., Bouet, V., Haelewyn, B., Boulouard, M., Schumann-Bard, P., & Freret, T. (2013) · Nature Protocols · doi:10.1038/nprot.2013.155 · Cited by 1,357 · see citing works
Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease
Wang, X., Wang, W., Li, L., Perry, G., Lee, H.-G., & Zhu, X. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.10.015 · Cited by 1,357 · see citing works
Physical Activity, Including Walking, and Cognitive Function in Older Women
Weuve, J. (2004) · JAMA · doi:10.1001/jama.292.12.1454 · Cited by 1,175 · see citing works
Mitochondrial dysfunction in cell senescence and aging
Miwa, S., Kashyap, S., Chini, E., & von Zglinicki, T. (2022) · Journal of Clinical Investigation · doi:10.1172/jci158447 · Cited by 1,061 · see citing works
Johnson, E. C. B., Dammer, E. B., Duong, D. M., Ping, L., Zhou, M., Yin, L., Higginbotham, L. A., Guajardo, A., White, B., Troncoso, J. C., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0815-6 · Cited by 1,001 · see citing works
Camacho-Pereira, J., Tarragó, M. G., Chini, C. C. S., Nin, V., Escande, C., Warner, G. M., Puranik, A. S., Schoon, R. A., Reid, J. M., Galina, A., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.006 · Cited by 901 · see citing works
Park, M. W., Cha, H. W., Kim, J., Kim, J. H., Yang, H., Yoon, S., Boonpraman, N., Yi, S. S., Yoo, I. D., & Moon, J.-S. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101947 · Cited by 683 · cited 1× · see citing works
“It is well known that mitochondrial structural damage and secondary oxidative damage have been implicated in the pathological process of AD [24 – 26].”
A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy
Ruas, J. L., White, J. P., Rao, R. R., Kleiner, S., Brannan, K. T., Harrison, B. C., Greene, N. P., Wu, J., Estall, J. L., Irving, B. A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.10.050 · Cited by 677 · see citing works
Transcellular degradation of axonal mitochondria
Davis, C.-H. O., Kim, K.-Y., Bushong, E. A., Mills, E. A., Boassa, D., Shih, T., Kinebuchi, M., Phan, S., Zhou, Y., Bihlmeyer, N. A., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1404651111 · Cited by 673 · see citing works
Physical exercise in the prevention and treatment of Alzheimer's disease
la Rosa, A. D., González, G. O., Arc‐Chagnaud, C., Millán-Domingo, F., Salvador‐Pascual, A., García-Lucerga, C., Blasco-Lafarga, C., García-Domínguez, E., Carretero, A., Correas, Á. G., et al. (2020) · Journal of sport and health science/Journal of Sport and Health Science · doi:10.1016/j.jshs.2020.01.004 · Cited by 617 · see citing works
Jackson, M. V., Morrison, T. J., Doherty, D. F., McAuley, D. F., Matthay, M. A., Kissenpfennig, A., O'Kane, C. M., & Krasnodembskaya, A. D. (2016) · Stem Cells · doi:10.1002/stem.2372 · Cited by 582 · see citing works
Maintenance of Skeletal Muscle Mitochondria in Health, Exercise, and Aging
Hood, D. A., Memme, J. M., Oliveira, A. N., & Triolo, M. (2019) · Annual Review of Physiology · doi:10.1146/annurev-physiol-020518-114310 · Cited by 567 · see citing works
Exercise-Mediated Neurogenesis in the Hippocampus via BDNF
Liu, P. Z., & Nusslock, R. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00052 · Cited by 533 · see citing works
Masuzawa, A., Black, K. M., Pacak, C. A., Ericsson, M., Barnett, R. J., Drumm, C., Seth, P., Bloch, D. B., Levitsky, S., Cowan, D. B., et al. (2013) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00883.2012 · Cited by 487 · see citing works
Butterfield, D. A., & Boyd-Kimball, D. (2018) · Journal of Alzheimer’s Disease · doi:10.3233/jad-170543 · Cited by 403 · see citing works
Intercellular mitochondrial transfer as a means of tissue revitalization
Liu, D., Gao, Y., Liu, J., Huang, Y., Yin, J., Feng, Y., Shi, L., Meloni, B. P., Zhang, C., Zheng, M., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00440-z · Cited by 403 · see citing works
Self-citationThe role of astroglia in neuroprotection
Bélanger, M., & Magistretti, P. J. (2009) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2009.11.3/mbelanger · Cited by 396 · see citing works
Sarnyai, Z., Sibille, E. L., Pavlides, C., Fenster, R. J., McEwen, B. S., & Tóth, M. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.26.14731 · Cited by 396 · see citing works
Brestoff, J. R., Wilen, C. B., Moley, J. R., Li, Y., Zou, W., Malvin, N. P., Rowen, M. N., Saunders, B. T., Ma, H., Mack, M. R., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.11.008 · Cited by 393 · see citing works
Tarragó, M. G., Chini, C. C. S., Kanamori, K. S., Warner, G. M., Caride, A., de Oliveira, G. C., Rud, M., Samani, A., Hein, K. Z., Huang, R., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.03.016 · Cited by 384 · see citing works
Song, T., Song, X., Zhu, C., Patrick, R., Skurla, M., Santangelo, I., Green, M., Harper, D., Ren, B., Forester, B. P., et al. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101503 · Cited by 346 · see citing works
Exercise and mitochondrial health
Memme, J. M., Erlich, A. T., Phukan, G., & Hood, D. A. (2021) · The Journal of Physiology · doi:10.1113/jp278853 · Cited by 343 · see citing works
Mi, Y., Qi, G., Vitali, F., Shang, Y., Raikes, A. C., Wang, T., Jin, Y., Brinton, R. D., Gu, H., & Yin, F. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00756-4 · Cited by 343 · see citing works
Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired
Liang, W., Sagar, S., Ravindran, R., Najor, R. H., Quiles, J. M., Chi, L., Diao, R. Y., Woodall, B. P., Leon, L. J., Zumaya, E., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40680-5 · Cited by 273 · see citing works
GAP43-dependent mitochondria transfer from astrocytes enhances glioblastoma tumorigenicity
Watson, D. C., Bayık, D., Storevik, S., Moreino, S. S., Sprowls, S. A., Han, J., Augustsson, M. T., Lauko, A. J., Palavalasa, S., Røsland, G. V., et al. (2023) · Nature Cancer · doi:10.1038/s43018-023-00556-5 · Cited by 254 · see citing works
Astrocyte dysfunction in Alzheimer disease
Acosta, C., Anderson, H. D., & Anderson, C. M. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.24075 · Cited by 248 · see citing works
Müller, W. E., Eckert, A., Kurz, C., Eckert, G. P., & Leuner, K. (2010) · Molecular Neurobiology · doi:10.1007/s12035-010-8141-5 · Cited by 243 · see citing works
Sun, C., Liu, X., Wang, B., Wang, Z., Liu, Y., Di, C., Si, J., Li, H., Wu, Q., Xu, D., et al. (2019) · Theranostics · doi:10.7150/thno.33100 · Cited by 214 · see citing works
Ni, X.-C., Wang, H.-F., Cai, Y.-Y., Yang, D., Alolga, R. N., Liu, B., Li, J., & Huang, F.-Q. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102363 · Cited by 203 · see citing works
Mitochondrial heterogeneity and homeostasis through the lens of a neuron
Pekkurnaz, G., & Wang, X. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00594-w · Cited by 195 · see citing works
Chakraborty, R., Nonaka, T., Hasegawa, M., & Zurzolo, C. (2023) · Cell Death & Disease · doi:10.1038/s41419-023-05835-8 · Cited by 190 · see citing works
MitoTimer: A novel tool for monitoring mitochondrial turnover
Hernandez, G., Thornton, C., Stotland, A., Lui, D., Sin, J., Ramil, J., Magee, N., Andres, A., Quarato, G., Carreira, R. S., et al. (2013) · Autophagy · doi:10.4161/auto.26501 · Cited by 187 · see citing works
Inter and Intracellular mitochondrial trafficking in health and disease
Shanmughapriya, S., Langford, D., & Natarajaseenivasan, K. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101128 · Cited by 171 · see citing works
López-Ortiz, S., Valenzuela, P. L., Seisdedos, M. M., Morales, J. S., Vega, T., Castillo-García, A., Nisticò, R., Mercuri, N. B., Lista, S., Lucia, A., et al. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101479 · Cited by 152 · 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
Chini, C., Hogan, K. A., Warner, G. M., Tarragó, M. G., Peclat, T. R., Tchkonia, T., Kirkland, J. L., & Chini, E. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.03.199 · Cited by 138 · see citing works
Exercise and metformin counteract altered mitochondrial function in the insulin-resistant brain
Ruegsegger, G. N., Vanderboom, P. M., Dasari, S., Klaus, K. A., Kabiraj, P., McCarthy, C. B., Lucchinetti, C. F., & Nair, K. S. (2019) · JCI Insight · doi:10.1172/jci.insight.130681 · Cited by 137 · see citing works
Bellaver, B., Souza, D. G., Souza, D. O., & Quincozes-Santos, A. (2017) · Molecular Neurobiology · doi:10.1007/s12035-016-9880-8 · Cited by 135 · see citing works
Physical Exercise and Selective Autophagy: Benefit and Risk on Cardiovascular Health
Wu, N. N., Tian, H., Chen, P., Wang, D., Ren, J. T., & Zhang, Y. (2019) · Cells · doi:10.3390/cells8111436 · Cited by 130 · see citing works
Arachidonic acid stimulates glucose uptake in cerebral cortical astrocytes.
Yu, N., Martin, J., Stella, N., & Magistretti, P. J. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.9.4042 · Cited by 120 · see citing works
Mareninova, O. A., Jia, W., Gretler, S. R., Holthaus, C. L., Thomas, D. D. H., Pimienta, M., Dillon, D. L., Gukovskaya, A. S., Gukovsky, I., & Groblewski, G. E. (2020) · Autophagy · doi:10.1080/15548627.2020.1715047 · Cited by 118 · see citing works
Xu, X., Shen, X., Wang, J., Feng, W., Wang, M., Miao, X., Wu, Q., Wu, L., Wang, X., Ma, Y., et al. (2021) · Aging Cell · doi:10.1111/acel.13465 · Cited by 103 · see citing works
Transfer of mitochondria and endosomes between cells by gap junction internalization
Norris, R. P. (2021) · Traffic · doi:10.1111/tra.12786 · Cited by 98 · see citing works
Neuron-astrocyte transmitophagy is altered in Alzheimer's disease
Lampinen, R., Belaya, I., Saveleva, L., Liddell, J. R., Rait, D., Huuskonen, M. T., Giniatullina, R., Sorvari, A., Soppela, L., Mikhailov, N., et al. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105753 · Cited by 97 · see citing works
Saraulli, D., Costanzi, M., Mastrorilli, V., & Vecchioli, S. F. (2017) · Current Neuropharmacology · doi:10.2174/1570159x14666160412150223 · Cited by 96 · see citing works
Lee, H., Cho, S., Kim, M.-J., Park, Y. J., Cho, E., Jo, Y. S., Kim, Y.-S., Lee, J. Y., Thoudam, T., Woo, S.-H., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113183 · Cited by 93 · see citing works
Electron tomographic analysis of synaptic ultrastructure
Burette, A. C., Lesperance, T., Crum, J., Martone, M., Volkmann, N., Ellisman, M. H., & Weinberg, R. J. (2012) · Journal of Comparative Neurology · doi:10.1002/cne.23067 · Cited by 85 · see citing works
Metabolic Contribution and Cerebral Blood Flow Regulation by Astrocytes in the Neurovascular Unit
Takahashi, S. (2022) · Cells · doi:10.3390/cells11050813 · Cited by 85 · see citing works
Galea, E., Weinstock, L. D., Larramona-Arcas, R., Pybus, A. F., Giménez-Llort, L., Escartin, C., & Wood, L. B. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105655 · Cited by 83 · see citing works
Ca2+ signaling, mitochondria and sensitivity to oxidative stress in aging astrocytes
Lin, D., Wu, J., Holstein, D. M., Upadhyay, G., Rourk, W., Muller, E., & Lechleiter, J. D. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.11.004 · Cited by 76 · see citing works
The Role of PGC-1α-Mediated Mitochondrial Biogenesis in Neurons
Chen, M., Yan, R., Luo, J.-S., Ning, J., Zhou, R., & Ding, L. (2023) · Neurochemical Research · doi:10.1007/s11064-023-03934-8 · Cited by 64 · see citing works
Mitochondria Transfer in Brain Injury and Disease
Fairley, L. H., Grimm, A., & Eckert, A. (2022) · Cells · doi:10.3390/cells11223603 · Cited by 63 · see citing works
Aβ promotes CD38 expression in senescent microglia in Alzheimer’s disease
Hu, Y., Huang, Y., Xing, S., Chen, C., Shen, D., & Chen, J. (2022) · Biological Research · doi:10.1186/s40659-022-00379-1 · Cited by 55 · see citing works
Hattori, T., Kaji, M., Ishii, H., Jureepon, R., Takarada-Iemata, M., Minh Ta, H., Manh Le, T., Konno, A., Hirai, H., Shiraishi, Y., et al. (2017) · Glia · doi:10.1002/glia.23139 · Cited by 53 · see citing works
Zhang, K.-L., Li, S.-J., Pu, X.-Y., Wu, F.-F., Liu, H., Wang, R.-Q., Liu, B.-Z., Li, Z., Li, K.-F., Qian, N.-S., et al. (2022) · Redox Biology · doi:10.1016/j.redox.2021.102216 · Cited by 52 · see citing works
Zheng, F., Luo, Z., Lin, X., Wang, W., Aschner, M., Cai, P., Wang, Y., Shao, W., Yu, G., Guo, Z., et al. (2021) · Nanotoxicology · doi:10.1080/17435390.2022.2026515 · Cited by 52 · see citing works
On Aerobic Exercise and Behavioral and Neural Plasticity
Swain, R., Berggren, K. L., Kerr, A. L., Patel, A. U., Peplinski, C., & Sikorski, A. M. (2012) · Brain Sciences · doi:10.3390/brainsci2040709 · Cited by 44 · see citing works
Maintenance of NAD+ Homeostasis in Skeletal Muscle during Aging and Exercise
Ji, L. L., & Yeo, D. (2022) · Cells · doi:10.3390/cells11040710 · Cited by 43 · see citing works
Wang, Y., Ni, J., Gao, T., Gao, C., Guo, L., & Yin, X. (2020) · Glia · doi:10.1002/glia.23850 · Cited by 42 · see citing works
Effects of O-GlcNAcylation on functional mitochondrial transfer from astrocytes
Park, J.-H., Nakamura, Y., Li, W., Hamanaka, G., Arai, K., Lo, E. H., & Hayakawa, K. (2021) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x20969588 · Cited by 42 · see citing works
Activating Autophagy by Aerobic Exercise in Mice
Rocchi, A., & He, C. (2017) · Journal of Visualized Experiments · doi:10.3791/55099 · Cited by 39 · see citing works
Wu, W., Yuan, S., Tang, Y., Meng, X., Peng, M., Hu, Z., & Liu, W. (2023) · Nutrients · doi:10.3390/nu15132851 · Cited by 26 · see citing works
Fu, S., Qin, L., Leung, C. T., Chan, B. P., & Chan, K. M. (2003) · Canadian Journal of Applied Physiology · doi:10.1139/h03-027 · Cited by 21 · see citing works
Kowalska, A., Pruchnik-Wolińska, D., Florczak, J., Szczech, J., Kozubski, W. P., Rossa, G., & Wender, M. (2004) · PubMed · Cited by 19 · see citing works
Park, D.-R., Nam, T.-S., Kim, Y.-W., Lee, S.-H., & Kim, U.-H. (2018) · Cellular Physiology and Biochemistry · doi:10.1159/000489441 · Cited by 19 · see citing works
Late Passage Cultivation Induces Aged Astrocyte Phenotypes in Rat Primary Cultured Cells
Bang, M., Gonzales, E. L., Shin, C. Y., & Kwon, K. J. (2021) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2020.175 · Cited by 19 · see citing works
Senescent Phenotype of Astrocytes Leads to Activation of BV2 Microglia and N2a Neuronal Cells Death
Zhang, W., Yang, X., Liu, J., Pan, Y., Zhang, M., & Chen, L. (2022) · Molecules · doi:10.3390/molecules27185925 · Cited by 16 · see citing works
Oxidative stress is associated with Aβ accumulation in chronic sleep deprivation model
Beiyu, Z., Zhou, R., Zhao, Y., Wei, S., Peng, L., Meng, W., Peng, W., Yuan, Y., & Qu, Q. (2024) · Brain Research · doi:10.1016/j.brainres.2024.148776 · Cited by 16 · see citing works
Identification and Characterization of Amyloid-β Accumulation in Synaptic Mitochondria
Yan, S. F., Akhter, F., Sosunov, A. A., & Yan, S. S. (2018) · Methods in Molecular Biology · doi:10.1007/978-1-4939-7816-8_25 · Cited by 15 · see citing works
MiRNA-494-3p Regulates Bupivacaine-Induced Neurotoxicity by the CDK6-PI3K/AKT Signaling
Zhang, L., Zhang, L., & Guo, F. (2021) · Neurotoxicity Research · doi:10.1007/s12640-021-00427-w · Cited by 15 · see citing works
Spatial transcriptomics shows moxibustion promotes hippocampus astrocyte and neuron interaction
Zhang, N., Shen, Y., Zhu, W., Li, C., Liu, S., Li, H., Wang, Y., Wang, J., Zhang, Q., Sun, J., et al. (2022) · Life Sciences · doi:10.1016/j.lfs.2022.121052 · Cited by 14 · see citing works
Activating Autophagy by Aerobic Exercise in Mice
Rocchi, A., & He, C. (2017) · Journal of Visualized Experiments · doi:10.3791/55099-v · Cited by 13 · see citing works
Xie, Y., Zhang, Y., Sun, A., Peng, Y., Hou, W., Xiang, C., Zhang, G., Lai, B., Hou, X., Zheng, F., et al. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102447 · Cited by 13 · see citing works
Methamphetamine induces cardiomyopathy through GATA4/NF-κB/SASP axis-mediated cellular senescence
Zhao, X., Lu, J., Zhang, C., Chen, C., Zhang, M., Zhang, J., Du, Q., & Wang, H. (2023) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2023.116457 · Cited by 12 · see citing works
Qin, Y., Pan, S.-Y., Dai, J.-R., Wang, Q., Luo, X., Qin, Z., & Luo, L. (2023) · Experimental Gerontology · doi:10.1016/j.exger.2023.112226 · Cited by 12 · see citing works
Li, J., Chang, W., Qin, G., Wojcik, K. R., Li, C., Hsu, C., Han, M., Zhu, X., Hoek, T. L. V., & Shao, Z. (2022) · The American Journal of Chinese Medicine · doi:10.1142/s0192415x22500513 · Cited by 6 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Karasek M, 2004, Ultrastructure of the central nervous system: the basics, Folia Neuropathol, 42, 1
Cited by
Sorted by citations
Ramos‐Jiménez, A., Rubio-Valles, M., Ramos-Hernández, J. A., González-Rodríguez, E., & Moreno-Brito, V. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26178697 · Cited by 20 · see citing works
Dembitskaya, Y., & Popov, A. (2025) · Metabolic Brain Disease · doi:10.1007/s11011-025-01706-7 · Cited by 7 · see citing works
Disrupted astrocyte-neuron signaling reshapes brain activity in epilepsy and Alzheimer’s disease
Wu, M., Zhang, R., Fu, P., & Mei, Y. (2025) · Neuroscience · doi:10.1016/j.neuroscience.2025.02.029 · Cited by 6 · see citing works
The potential of mitochondrial transfer as the modifying therapy for osteoarthritis
He, Y., Wang, X., Xu, B., Chen, S., Li, H., Chang, B., Hu, C., Lan, X., Li, S., & Li, G. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1643141 · Cited by 5 · see citing works
The impact of exercise on brain mitochondrial health and its relevance to Alzheimer's disease
Csikós, V., Thyfault, J. P., & Wilkins, H. (2025) · Brain and Environment · doi:10.1016/j.braen.2025.100012 · Cited by 6 · see citing works
Liu, R., Deng, Q., Gong, L., & Yang, L. (2026) · Neuroscience Bulletin · doi:10.1007/s12264-026-01598-2 · Cited by 5 · see citing works
CD38-NAD(+) Axis: New Insights into Glaucoma Therapy
Zhang, W., Zheng, H., Pang, Y., Wang, Y., & Zhang, X. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05243-3 · Cited by 4 · see citing works
The role of mitochondrial transfer in lung disease
Yang, K., Luo, M., & Dong, W. (2025) · Respiratory Research · doi:10.1186/s12931-025-03408-1 · Cited by 4 · see citing works
Extracellular mitochondria: a potential player involved in exercise health benefits
Pedrosa, M. B., Santos, L. L., Ferreira, R. M. S., & Magalhães, J. S. (2025) · Biochimie · doi:10.1016/j.biochi.2025.12.011 · Cited by 3 · see citing works
Bo, W., Guo, Q., Zhu, W., & Ma, Y. (2026) · Antioxidants · doi:10.3390/antiox15050622 · Cited by 2 · see citing works
Abdelaziz, A. M., Shokr, M. M., Fathy, M. K., & Fawzy, M. N. (2026) · Journal of Molecular Neuroscience · doi:10.1007/s12031-026-02531-y · Cited by 2 · see citing works
Mitochondrial Fragmentation as a Key Driver of Neurodegenerative Disease
Chaplygina, A. V., & Zhdanova, D. (2025) · Current Alzheimer Research · doi:10.2174/0115672050366194250107050650 · Cited by 2 · see citing works
Anderson, G. (2026) · Exploration of neuroscience · doi:10.37349/en.2026.1006132 · Cited by 1 · see citing works
Shi, L., Xie, J.-D., Dai, T., Zhang, M.-Z., Yang, T., Sheng, L., Jin, Q., & Dai, J. (2026) · Frontiers in Physiology · doi:10.3389/fphys.2026.1827919 · Cited by 1 · see citing works
Zhang, R. X., & Chen, K. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1856546 · Cited by 1 · see citing works
Context‐Dependent Functional Outcomes of Mitochondrial Transfer: A Donor–Recipient Perspective
Wang, B., Lin, T., Mo, X., Mugaka, B. P., Tai, G., & Xu, M. (2026) · Advanced Biology · doi:10.1002/adbi.70137 · Cited by 1 · see citing works
Mitochondrial quality control as a unifying regulatory platform in inflammatory bone diseases
Dong, Z., Liu, C., Li, Y., Yang, T., Xiang, T., Wang, J., Chen, L., & Kou, X. (2026) · The Innovation Medicine · doi:10.59717/j.xinn-med.2026.100255 · Cited by 1 · see citing works
Hagiu, B.-A. (2025) · Medical Hypotheses · doi:10.1016/j.mehy.2025.111697
Mitochondrial transfer as a therapeutic target for peripheral neuropathy
Wei, J., & Wang, F. (2026) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2026.03.004
Mitochondria transfer-driven chemical sensing: FRET platforms for dynamic disease diagnostics
Zhang, W., You, J., Liu, H., Liu, C., Li, J., Zhang, Y., Huachen, Z., Hu, P., Li, D., & Huang, C. Z. (2026) · TrAC Trends in Analytical Chemistry · doi:10.1016/j.trac.2026.118839
Zhang, Y.-F., Zhao, D., Wei, J., Liang, X., Wang, L., Wang, J., Li-bin, J., Chen, J.-Y., Zhang, Y., & Liu, Y. (2026) · Translational Stroke Research · doi:10.1007/s12975-026-01446-5
Fritsch, E., Horvatović, K., Otte, P. S., Koudelka, T., Rossius, J., Braeuning, C., Breimann, L., Piazza, I., & Birol, M. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.19.733342
Singhal, G., & Baune, B. T. (2026) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2026.1859424
Exercise as a multidomain intervention in aging and Alzheimer’s disease: State of the evidence
Marinho, L. S. R., An, L. G. Y. G., Riva, G. S., Prado, S. P., Pongilio, R. P., Donnici, G. K., Chiovitti, C. S., & Kihara, A. H. (2026) · Aging advances. · doi:10.4103/agingadv.agingadv-d-26-00003
Autophagy as a mechanistic link between physical exercise and Alzheimer’s disease
Yu, Z., Wang, Y., & Yang, Y. (2026) · Neuroscience · doi:10.1016/j.neuroscience.2026.08.026
Ma, M., Tian, J., Wang, Z., Zhang, Z., Zhang, Y., & Hai, B. (2026) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2026.09.003
The impact of aging, sex, and exercise on brain mitochondria
Zhang, J., Darley-Usmar, V. M., & Li, Y. (2026) · Frontiers in Aging · doi:10.3389/fragi.2026.1920914
窦报敏, Chen, J., Zhao, H., Sun-Yan, A., Zhu, X., & Xu, Y. (2026) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2026.109130
Physical exercise: a multi-target strategy for the prevention and treatment of Alzheimer’s disease
佟乌云 (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1876075
Kao, S., Yousaf, F., Ishaq, S., Shah, I. A., Wu, B.-T., & Lee, S.-D. (2026) · Experimental Neurology · doi:10.1016/j.expneurol.2026.116070
- Authors
- Cai, J., Chen, Y., She, Y., He, X., Feng, H., Sun, H., Yin, M., Gao, J., Sheng, C., Li, Q., & Xiao, M.
- Affiliations
- Nanjing Brain Hospital (CN)
- Nanjing Medical University (CN)
- Jiangsu Province Hospital (CN)
- Corresponding author
- Li, Qian
- Xiao, Ming
- ORCID
- Venue
- Brain Pathology
- Publisher
- Wiley
- Published
- 2024-10-26
- Volume
- 35
- Issue
- 3
- Pages
- e13316-e13316
- ISSN
- 1015-6305 (ISSN-L)
- 1750-3639
- PMC
- PMC11961210
- OpenAlex
- W4403795009
- Semantic Scholar
- 2a41bba63564a5658f38ffe09915312bbf1db204
- Cited by
- 30
- References
- 82
- Citations by year
- 2026: 20 · 2025: 10
- FWCI
- 8.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Brain Pathology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81871117, 82471608)
- Natural Science Foundation of Jiangsu Province (BK20230057)
- 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 › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- aerobic exercise, Alzheimer's disease, astrocytes, mitochondrial quality control, astrocyte-neuron communication, CD38, 5xFAD mice, amyloid-beta, reactive oxygen species, oxidative stress, amyloid plaques, cognitive impairment, hippocampus, mitochondrial dysfunction
- MeSH terms
- Aerobiosis, Alzheimer Disease, Animals, Astrocytes, Atrophy, Cells, Cultured, Disease Models, Animal, Hippocampus, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Mitochondria, Neurons, Signal Transduction, Cellular Senescence, Oxidative Stress, Mice, ADP-ribosyl Cyclase 1
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 2026-11-02.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-02.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
