Rethinking of Alzheimer's disease: Lysosomal overloading and dietary therapy

Yuan, Shu; Jiang, Si‐Cong; Zhang, Zhongwei; Fu, Yu‐Fan; Yang, Xinyue; Li, Zi-Lin; Hu, Jing

doi:10.3389/fnagi.2023.1130658

Cited by 2 publications

(2 citation statements)

References 54 publications

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“…Modulation of autophagy as a therapeutic strategy for HD has been investigated in various cell and animal models of HD , Boland, Yu et al 2018, Kim, Lalonde et al 2021, Jiang, Handley et al 2023, Yang and Zhang 2023. Of particular relevance to our present study are those involving autophagy induction with mTOR-dependent or -independent autophagy-enhancing approaches in HD mouse models [e.g.…”

Section: Introductionmentioning

confidence: 93%

mTOR inhibition in Q175 Huntington’s disease model mice facilitates neuronal autophagy and mutant huntingtin clearance

Stavrides,

Goulbourne,

Peddy

et al. 2024

Preprint

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Huntington’s disease (HD) is caused by expansion of the polyglutamine stretch in huntingtin protein (HTT) resulting in hallmark aggresomes/inclusion bodies (IBs) composed of mutant huntingtin protein (mHTT) and its fragments. Stimulating autophagy to enhance mHTT clearance is considered a potential therapeutic strategy for HD. Our recent evaluation of the autophagic-lysosomal pathway (ALP) in human HD brain reveals upregulated lysosomal biogenesis and relatively normal autophagy flux in early Vonsattel grade brains, but impaired autolysosome clearance in late grade brains, suggesting that autophagy stimulation could have therapeutic benefits as an earlier clinical intervention. Here, we tested this hypothesis by crossing the Q175 HD knock-in model with our autophagy reporter mouse TRGL (Thy-1-RFP-GFP-LC3) to investigatein vivoneuronal ALP dynamics. In the Q175 and/or TRGL/Q175 mice, mHTT was detected in autophagic vacuoles and also exhibited high level colocalization with autophagy receptors p62/SQSTM1 and ubiquitin in the IBs. Compared to the robust lysosomal pathology in late-stage human HD striatum, ALP alterations in Q175 models are also late-onset but milder that included a lowered phospho-p70S6K level, lysosome depletion and autolysosome elevation including more poorly acidified autolysosomes and larger-sized lipofuscin granules, reflecting impaired autophagic flux. Administration of a mTOR inhibitor to 6-mo-old TRGL/Q175 normalized lysosome number, ameliorated aggresome pathology while reducing mHTT-, p62- and ubiquitin-immunoreactivities, suggesting beneficial potential of autophagy modulation at early stages of disease progression.

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Section: Introductionmentioning

confidence: 93%

mTOR inhibition in Q175 Huntington’s disease model mice facilitates neuronal autophagy and mutant huntingtin clearance

Stavrides,

Goulbourne,

Peddy

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Other studies on the five times familial AD (5XFAD) mouse model show that although rapamycin may attenuate memory deficits in five times familial AD mouse model (5XFAD) with seizure-induced exacerbation, treatment did not alter, or even increased, hippocampal Aβ42 levels ( Singh et al, 2017a ; Shi et al, 2022 ). A possible explanation suggested to this disparity between models is their relative lysosome capacities ( Carosi and Sargeant, 2023 ; Yuan et al, 2023 ). For instance, 5XFAD has less lysosomal degradation potential due to its mutant PSEN1 gene, which is known to interfere with the lysosomal biogenesis ( Carosi and Sargeant, 2023 ; J. H; Lee et al, 2022 ).…”

Section: Mtor Inhibition In Alzheimer’s Modelsmentioning

confidence: 99%

Pharmacological mTOR inhibitors in ameliorating Alzheimer’s disease: current review and perspectives

Xie,

Zheng,

Han

et al. 2024

Front. Pharmacol.

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Traditionally, pharmacological mammalian/mechanistic targets of rapamycin (mTOR) kinase inhibitors have been used during transplantation and tumor treatment. Emerging pre-clinical evidence from the last decade displayed the surprising effectiveness of mTOR inhibitors in ameliorating Alzheimer’s Disease (AD), a common neurodegenerative disorder characterized by progressive cognitive function decline and memory loss. Research shows mTOR activation as an early event in AD development, and inhibiting mTOR may promote the resolution of many hallmarks of Alzheimer’s. Aberrant protein aggregation, including amyloid-beta (Aβ) deposition and tau filaments, and cognitive defects, are reversed upon mTOR inhibition. A closer inspection of the evidence highlighted a temporal dependence and a hallmark-specific nature of such beneficial effects. Time of administration relative to disease progression, and a maintenance of a functional lysosomal system, could modulate its effectiveness. Moreover, mTOR inhibition also exerts distinct effects between neurons, glial cells, and endothelial cells. Different pharmacological properties of the inhibitors also produce different effects based on different blood-brain barrier (BBB) entry capacities and mTOR inhibition sites. This questions the effectiveness of mTOR inhibition as a viable AD intervention strategy. In this review, we first summarize the different mTOR inhibitors available and their characteristics. We then comprehensively update and discuss the pre-clinical results of mTOR inhibition to resolve many of the hallmarks of AD. Key pathologies discussed include Aβ deposition, tauopathies, aberrant neuroinflammation, and neurovascular system breakdowns.

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Rethinking of Alzheimer's disease: Lysosomal overloading and dietary therapy

Cited by 2 publications

References 54 publications

mTOR inhibition in Q175 Huntington’s disease model mice facilitates neuronal autophagy and mutant huntingtin clearance

mTOR inhibition in Q175 Huntington’s disease model mice facilitates neuronal autophagy and mutant huntingtin clearance

Pharmacological mTOR inhibitors in ameliorating Alzheimer’s disease: current review and perspectives

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