Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice

Caballero, Benjamı́n; Bourdenx, Mathieu; Luengo, Enrique; Díaz, Antonio; Sohn, Peter; Chen, Xu; Wang, Chao; Juste, Yves R.; Wegmann, Susanne; Patel, Bindi; Young, Zapporah T.; Kuo, Szu Yu; Rodríguez-Navarro, José Antonio; Shao, Hao; López, Manuela G.; Karch, Celeste M.; Goate, Alison; Gestwicki, Jason E.; Hyman, Bradley T.; Gan, Li; Cuervo, Ana María

doi:10.1038/s41467-021-22501-9

Cited by 117 publications

(97 citation statements)

References 91 publications

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“…However, recent studies revealed that other modifications of tau, such as acetyl-tau were also associated with the development of AD. The increased level of acetyl-tau affected the synapse and autophagy function associated with the memory deficits in AD [ 58 , 59 ]. Thus, the assessments of acetyl-tau expression after PM exposure in the future researches were needed.…”

Section: Discussionmentioning

confidence: 99%

Three month inhalation exposure to low-level PM2.5 induced brain toxicity in an Alzheimer’s disease mouse model

et al. 2021

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Although numerous epidemiological studies revealed an association between ambient fine particulate matter (PM2.5) exposure and Alzheimer’s disease (AD), the PM2.5-induced neuron toxicity and associated mechanisms were not fully elucidated. The present study assessed brain toxicity in 6-month-old female triple-transgenic AD (3xTg-AD) mice following subchronic exposure to PM2.5 via an inhalation system. The treated mice were whole-bodily and continuously exposed to real-world PM2.5 for 3 months, while the control mice inhaled filtered air. Changes in cognitive and motor functions were evaluated using the Morris Water Maze and rotarod tests. Magnetic resonance imaging analysis was used to record gross brain volume alterations, and tissue staining with hematoxylin and eosin, Nissl, and immunohistochemistry methods were used to monitor pathological changes in microstructures after PM2.5 exposure. The levels of AD-related hallmarks and the oxidative stress biomarker malondialdehyde (MDA) were assessed using Western blot analysis and liquid chromatography-mass spectrometry, respectively. Our results showed that subchronic exposure to environmental levels of PM2.5 induced obvious neuronal loss in the cortex of exposed mice, but without significant impairment of cognitive and motor function. Increased levels of phosphorylated-tau and MDA were also observed in olfactory bulb or hippocampus after PM2.5 exposure, but no amyloid pathology was detected, as reported in previous studies. These results revealed that a relatively lower level of PM2.5 subchronic exposure from the environmental atmosphere still induced certain neurodegenerative changes in the brains of AD mice, especially in the olfactory bulb, entorhinal cortex and hippocampus, which is consistent with the nasal entry and spreading route for PM exposure. Systemic factors may also contribute to the neuronal toxicity. The effects of PM2.5 after a more prolonged exposure period are needed to establish a more comprehensive picture of the PM2.5-mediated development of AD.

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Section: Discussionmentioning

confidence: 99%

Three month inhalation exposure to low-level PM2.5 induced brain toxicity in an Alzheimer’s disease mouse model

et al. 2021

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“…Tau acetylation at K174, K274, and K281 have been demonstrated to inhibit synaptic transmission and promote memory deficits in vivo 11 , 12 . Tau acetylation can also regulate its degradation with acetylation of K274 and K281 selectively targeting macroautophagy, while increased pseudoacetylation of these sites exacerbate pathogenesis in some disease models 13 . Overall reduction of tau acetylation also improve outcomes in models of traumatic brain injury 14 .…”

Section: Introductionmentioning

confidence: 99%

Tau K321/K353 pseudoacetylation within KXGS motifs regulates tau–microtubule interactions and inhibits aggregation

Xia

Bell

2021

Sci Rep

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Alzheimer’s disease is the leading cause of dementia and a defining hallmark is the progressive brain deposition of tau aggregates. The insidious accumulation of brain tau inclusions is also involved in a group of neurodegenerative diseases termed frontotemporal dementias. In all of these disorders, tau aggregates are enriched in post-translational modifications including acetylation, which has recently been identified at multiple sites. While most evidence suggest that tau acetylation is detrimental and promotes tau aggregation, a few studies support that tau acetylation within the KXGS motif can be protective and inhibit tau aggregation. To model site-specific acetylation at K259, K290, K321, and K353, acetylmimetics were created by mutating lysine to glutamine residues, which approximates size and charge of acetylation. HEK293T cells were transfected to express wild type tau, tau pathogenic mutations (P301L and P301L/S320F) or tau acetylmimetics and assessed by cell-based assays for microtubule binding and tau aggregation. Acetylmimetics within the KXGS motif (K259Q, K290Q, K321Q, K353Q) leads to significant decreased tau–microtubule interactions. Acetylmimetics K321Q and K353Q within the context of the pathogenic P301L tau mutation strongly inhibited prion-like seeded aggregation. This protective effect was confirmed to decrease intrinsic aggregation of P301L/S320F tau double mutation. Surprisingly, K321Q and K353Q acetylmimetics altered the conformational structure of P301L/S320F tau to extensively impair Thioflavin S binding. Site-specific acetylation of tau at K321 and K353 could represent a natural protective mechanism against tau aggregation and could be a potential therapeutic target.

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“…However, full-length tau is preferentially digested through proteasomes [ 51 ]. Recently, it was proposed that a large fraction of tau is degraded by CMA, and upon acetylation, tau is preferentially degraded by macroautophagy and endocytic microautophagy [ 52 ].…”

Section: Tau Degradation Pathwaymentioning

confidence: 99%

“…Tang et al also reported that activated mTORC, which leads to autophagy inactivation, promotes tau secretion into the extracellular space in an exosome-independent manner in neuroblastoma cells, suggesting that tau release is mediated by mTORC via an exosome-free route ( Figure 6 ) [ 63 ]. Recently, it was also reported that CMA blockade upregulated cell to cell propagation in a rodent model of tauopathy [ 52 ].…”

Section: Tau Propagation Due To Autophagy Impairmentmentioning

confidence: 99%

Autophagy and Tau Protein

Hamano

Enomoto

Shirafuji

et al. 2021

IJMS

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Neurofibrillary tangles, which consist of highly phosphorylated tau protein, and senile plaques (SPs) are pathological hallmarks of Alzheimer’s disease (AD). In swollen axons, many autophagic vacuoles are observed around SP in the AD brain. This suggests that autophagy function is disturbed in AD. We used a neuronal cellular model of tauopathy (M1C cells), which harbors wild type tau (4R0N), to assess the effects of the lysosomotrophic agent NH4Cl, and autophagy inhibitors chloroquine and 3 methyladenine (3MA). It was found that chloroquine, NH4Cl and 3MA markedly increased tau accumulation. Thus, autophagy lysosomal system disturbances disturbed the degradation mechanisms of tau protein. Other studies also revealed that tau protein, including aggregated tau, is degraded via the autophagy lysosome system. Phosphorylated and C terminal truncated tau were also reported to disturb autophagy function. As a therapeutic strategy, autophagy upregulation was suggested. Thus far, as autophagy modulators, rapamycin, mTOCR1 inhibitor and its analogues, lithium, metformin, clonidine, curcumin, nicotinamide, bexaroten, and torehalose have been proposed. As a therapeutic strategy, autophagic modulation may be the next target of AD therapeutics.

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Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice

Cited by 117 publications

References 91 publications

Three month inhalation exposure to low-level PM2.5 induced brain toxicity in an Alzheimer’s disease mouse model

Three month inhalation exposure to low-level PM2.5 induced brain toxicity in an Alzheimer’s disease mouse model

Tau K321/K353 pseudoacetylation within KXGS motifs regulates tau–microtubule interactions and inhibits aggregation

Autophagy and Tau Protein

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