The Lysosome in Aging‐Related Neurodegenerative Diseases

Nixon, Ralph A.

doi:10.1002/9781118978320.ch9

Cited by 4 publications

(3 citation statements)

References 343 publications

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“…Abnormally phosphorylated and otherwise post-translationally modified tau has also received significant attention, as it is a primary constituent of neurofibrillary tangles (NFTs) and neuropil threads that are observed within neurons in partially overlapping brain regions of people with AD . The accumulation of pathologic tau is a better predictor of dementia, and recent work has shown that phosphorylated tau at positions 217, 181, and 205 indicates staging and development of AD with translation to reliable plasma markers that also correlate with the degree of dementia. , In addition, there are many other pathologic changes that accompany AD, including other aggregated deposits such as Lewy bodies, vascular disease, energy deficiency, and lysosomal storage. , The relationships between all of these observations and their underlying causes remain to be fully elucidated, but it is clear that in the absence of genetic predisposition, increasing age is the primary risk factor for AD …”

Section: Introductionmentioning

confidence: 99%

“…10,11 In addition, there are many other pathologic changes that accompany AD, including other aggregated deposits such as Lewy bodies, 12 vascular disease, 13 energy deficiency, 14 and lysosomal storage. 15,16 The relationships between all of these observations and their underlying causes remain to be fully elucidated, but it is clear that in the absence of genetic predisposition, increasing age is the primary risk factor for AD. 17 One aspect of aging that remains underexplored is the spontaneous chemical modification (SCM) of long-lived proteins.…”

Section: ■ Introductionmentioning

confidence: 99%

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Does Data-Independent Acquisition Data Contain Hidden Gems? A Case Study Related to Alzheimer’s Disease

et al. 2021

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One of the potential benefits of using data-independent acquisition (DIA) proteomics protocols is that information not originally targeted by the study may be present and discovered by subsequent analysis. Herein, we reanalyzed DIA data originally recorded for global proteomic analysis to look for isomerized peptides, which occur as a result of spontaneous chemical modifications to long-lived proteins. Examination of a large set of human brain samples revealed a striking relationship between Alzheimer's disease (AD) status and isomerization of aspartic acid in a peptide from tau. Relative to controls, a surprising increase in isomer abundance was found in both autosomal dominant and sporadic AD samples. To explore potential mechanisms that might account for these observations, quantitative analysis of proteins related to isomerization repair and autophagy was performed. Differences consistent with reduced autophagic flux in AD-related samples relative to controls were found for numerous proteins, including most notably p62, a recognized indicator of autophagic inhibition. These results suggest, but do not conclusively demonstrate, that lower autophagic flux may be strongly associated with loss of function in AD brains. This study illustrates that DIA data may contain unforeseen results of interest and may be particularly useful for pilot studies investigating new research directions. In this case, a promising target for future investigations into the therapy and prevention of AD has been identified.

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Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Does Data-Independent Acquisition Data Contain Hidden Gems? A Case Study Related to Alzheimer’s Disease

et al. 2021

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“…5,6 In addition, there are many other pathologic changes that accompany AD, including other aggregated deposits such as Lewy bodies, 7 vascular disease, 8 energy deficiency, 9 and lysosomal storage. 10,11 The relationships between all of these observations and their underlying causes remain to be fully elucidated, but it is clear that absent genetic predisposition, increasing age is the primary risk factor for AD. 12 One aspect of aging that remains underexplored is the spontaneous chemical modification (SCM) of longlived proteins.…”

Section: Introductionmentioning

confidence: 99%

Spontaneous Isomerization of Asp387 in Tau is Diagnostic for Alzheimer’s Disease: An Endogenous Indicator of Reduced Autophagic Flux

et al. 2021

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Amino acid isomerization is a spontaneous chemical modification potentially related to the underlying causes of Alzheimer's disease (AD). We demonstrate that data-independent acquisition mass spectrometry can be used to characterize isomerization in complex protein mixtures. Examination of a large cohort of brain tissue samples revealed a striking relationship between isomerization of tau and AD status. Surprisingly, isomerization was found to be more abundant in both autosomal dominant and sporadic AD samples relative to controls. We hypothesize that lower autophagic flux in AD brains accounts for these results. Additional data, including quantitative analysis of proteins related to autophagy, strongly support this hypothesis. For example, isomerization of tau is positively correlated with levels of p62, a recognized indicator of autophagic inhibition. In sum, the data suggest strong ties between isomerization and autophagic flux, which may therefore represent a promising target for future investigations into the therapy and prevention of AD.

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