Dynamic changes of autophagic flux induced by Abeta in the brain of postmortem Alzheimer’s disease patients, animal models and cell models

Long, Zhimin; Chen, Jingfei; Zhao, Yating; Zhou, Wen; Yao, Qiuhui; Wang, Yingxiong; He, Guiqiong

doi:10.18632/aging.103305

Cited by 33 publications

(16 citation statements)

References 52 publications

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“…Autophagy dysregulation has been reported in AD brain, which contributes to the formation of AD pathologies [ 31 ]. Therefore, we investigated the involvement of autophagy in the accumulation of Aβ plaques and NP tau pathology in APP/PS1 mice.…”

Section: Resultsmentioning

confidence: 99%

Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice

et al. 2021

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Background The neuropathological hallmarks of Alzheimer’s disease (AD) are amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). The amyloid cascade theory is the leading hypothesis of AD pathology. Aβ deposition precedes the aggregation of tau pathology and Aβ pathology precipitates tau pathology. Evidence also indicates the reciprocal interactions between amyloid and tau pathology. However, the detailed relationship between amyloid and tau pathology in AD remains elusive. Metformin might have a positive effect on cognitive impairments. However, whether metformin can reduce AD-related pathologies is still unconclusive. Methods Brain extracts containing tau aggregates were unilaterally injected into the hippocampus and the overlying cerebral cortex of 9-month-old APPswe/PS1DE9 (APP/PS1) mice and age-matched wild-type (WT) mice. Metformin was administrated in the drinking water for 2 months. Aβ pathology, tau pathology, plaque-associated microgliosis, and autophagy marker were analyzed by immunohistochemical staining and immunofluorescence analysis 2 months after injection of proteopathic tau seeds. The effects of metformin on both pathologies were explored. Results We observed tau aggregates in dystrophic neurites surrounding Aβ plaques (NP tau) in the bilateral hippocampi and cortices of tau-injected APP/PS1 mice but not WT mice. Aβ plaques promoted the aggregation of NP tau pathology. Injection of proteopathic tau seeds exacerbated Aβ deposits and decreased the number of microglia around Aβ plaques in the hippocampus and cortex of APP/PS1 mice. Metformin ameliorated the microglial autophagy impairment, increased the number of microglia around Aβ plaques, promoted the phagocytosis of NP tau, and reduced Aβ load and NP tau pathology in APP/PS1 mice. Conclusion These findings indicate the existence of the crosstalk between amyloid and NP tau pathology. Metformin promoted the phagocytosis of pathological Aβ and tau proteins by enhancing microglial autophagy capability. It reduced Aβ deposits and limited the spreading of NP tau pathology in APP/PS1 mice, which exerts a beneficial effect on both pathologies.

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Section: Resultsmentioning

confidence: 99%

Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice

et al. 2021

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“…Our results were consistent with reports by Zhao et al that decreased levels of autophagic‐related genes and autophagic flux were examined in 9‐month‐old and 12‐month‐old transgenic AD mice (Manczak et al, 2018; Zhao et al, 2020). However, it is controversial because some studies indicate an increased autophagic level in 4‐ to 6‐month‐old AD mice (Long et al, 2020; Sanchez‐Varo et al, 2012). The differences of these observations might be attributed to the age‐dependent down‐regulated expression of autophagy‐related genes following the pathology progression in AD (Omata et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Activation of CREB‐mediated autophagy by thioperamide ameliorates β‐amyloid pathology and cognition in Alzheimer’s disease

Wang

Liu

et al. 2021

Aging Cell

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Alzheimer's disease (AD) is an age‐related neurodegenerative disease, and the imbalance between production and clearance of β‐amyloid (Aβ) is involved in its pathogenesis. Autophagy is an intracellular degradation pathway whereby leads to removal of aggregated proteins, up‐regulation of which may be a plausible therapeutic strategy for the treatment of AD. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Our previous study showed that thioperamide, as an antagonist of H3R, enhances autophagy and protects against ischemic injury. However, the effect of thioperamide on autophagic function and Aβ pathology in AD remains unknown. In this study, we found that thioperamide promoted cognitive function, ameliorated neuronal loss, and Aβ pathology in APP/PS1 transgenic (Tg) mice. Interestingly, thioperamide up‐regulated autophagic level and lysosomal function both in APP/PS1 Tg mice and in primary neurons under Aβ‐induced injury. The neuroprotection by thioperamide against AD was reversed by 3‐MA, inhibitor of autophagy, and siRNA of Atg7, key autophagic‐related gene. Furthermore, inhibition of activity of CREB, H3R downstream signaling, by H89 reversed the effect of thioperamide on promoted cell viability, activated autophagic flux, and increased autophagic‐lysosomal proteins expression, including Atg7, TFEB, and LAMP1, suggesting a CREB‐dependent autophagic activation by thioperamide in AD. Taken together, these results suggested that H3R antagonist thioperamide improved cognitive impairment in APP/PS1 Tg mice via modulation of the CREB‐mediated autophagy and lysosomal pathway, which contributed to Aβ clearance. This study uncovered a novel mechanism involving autophagic regulating behind the therapeutic effect of thioperamide in AD.

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“…Many studies have shown that AD pathogenesis is accompanied by autophagic disorder (Peric and Annaert, 2015 ; Zhang et al, 2016 ), which may occur in different stages of autophagic flux. In our previous study, we explored the function of autophagic flux in AD (Long et al, 2020 ). Immunofluorescence staining showed that autophagosomes accumulated in the brain tissues of AD patients, and the lysosomal marker Lamp1 was decreased.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Autolysosomal Function Ameliorates the Inflammatory Response Mediated by the NLRP3 Inflammasome in Alzheimer’s Disease

Zhou

Deng

Zhao

et al. 2021

Front. Aging Neurosci.

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The pathogenesis of Alzheimer’s disease (AD) involves activation of many NLRP3 inflammatory bodies, which may be related to amyloid β peptide and aggregation of misfolded proteins. Autophagy is an important regulator of inflammatory bodies. However, autophagy shows dynamic changes in the development of AD, and its role in inflammation remains controversial. In this study, the key link between autophagic disorders and the NLRP3 inflammasome in AD was investigated. APP/PS1 double transgenic mice and C57 mice with Aβ25–35 injected into the lateral ventricle were used as two animal models of AD. Immunofluorescence staining and Western blot analysis showed that NLRP3 inflammasome-related proteins and inflammatory cytokines, such as IL-1α, IL-1β, IL-6, IL-12, and TNF-α, were increased and microglia were activated in the brains of both AD animal models. Endogenous overexpression of the APPswe gene and exogenous addition of Aβ25–35 increased the expression of NLRP3 inflammasome-related proteins, while exogenous Aβ25–35 intervention more significantly activated inflammation. Furthermore, LC3 was increased in the AD animal and cell models, and the level of Lamp1 decreased. After overexpression of the primary regulator of lysosomal biogenesis, TFEB, the lysosome protein Lamp1 was increased, and LC3 and inflammatory protein expression were decreased. These results suggest that the NLRP3 inflammasome-mediated inflammatory response is activated in AD animal and cell models, which may be related to the decline in autolysosome function. Overexpression of the TFEB protein can reduce the inflammatory response by improving autolysosome function in AD model cells.

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Dynamic changes of autophagic flux induced by Abeta in the brain of postmortem Alzheimer’s disease patients, animal models and cell models

Cited by 33 publications

References 52 publications

Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice

Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice

Activation of CREB‐mediated autophagy by thioperamide ameliorates β‐amyloid pathology and cognition in Alzheimer’s disease

Enhanced Autolysosomal Function Ameliorates the Inflammatory Response Mediated by the NLRP3 Inflammasome in Alzheimer’s Disease

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