TY - JOUR
T1 - Preserved autophagy in cognitively intact non-demented individuals with Alzheimer's neuropathology
AU - Tumurbaatar, Batbayar
AU - Fracassi, Anna
AU - Scaduto, Pietro
AU - Guptarak, Jutatip
AU - Woltjer, Randall
AU - Jupiter, Daniel
AU - Taglialatela, Giulio
N1 - Funding Information:
The authors thank the Allen Institute for Brain Science for making all data publicly available. The authors also thank Ms Wen‐Ru Zhang for her technical assistance and Dr Stacy Sell for the helpful comments and for the support during the editing of the manuscript. The authors declare that the work was supported by NIH/NIA grants: AG060718 and AG073133 to GT; NIH/NIA grant: 5P30AG066518 to RW; Alzheimer's Association Research Fellowship: AARF22973974 to AF.
Publisher Copyright:
© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
PY - 2023
Y1 - 2023
N2 - INTRODUCTION: Growing evidence supports that dysfunctional autophagy, the major cell mechanism responsible for removing protein aggregates and a route of clearance for Tau in healthy neurons, is a major finding in demented Alzheimer's disease (AD) patients. However, the association of autophagy with maintenance of cognitive integrity in resilient individuals who have AD neuropathology but remain non-demented (NDAN) has not been evaluated. METHODS: Using post mortem brain samples from age-matched healthy control, AD, and NDAN subjects, we evaluated autophagy in relation to Tau pathology using Western blot, immunofluorescence and RNA-seq. RESULTS: Compared to AD patients, NDAN subjects had preserved autophagy and reduced tauopathy. Furthermore, expression of autophagy genes and AD-related proteins were significantly associated in NDAN compared to AD and control subjects. DISCUSSION: Our results suggest preserved autophagy is a protective mechanism that maintains cognitive integrity in NDAN individuals. This novel observation supports the potential of autophagy-inducing strategies in AD therapeutics. Highlights: NDAN subjects have preserved autophagic protein levels comparable with control subjects. Compared to control subjects, NDAN subjects have significantly reduced Tau oligomers and PHF Tau phosphorylation at synapses that negatively correlate with autophagy markers. Transcription of autophagy genes strongly associates with AD-related proteins in NDAN donors.
AB - INTRODUCTION: Growing evidence supports that dysfunctional autophagy, the major cell mechanism responsible for removing protein aggregates and a route of clearance for Tau in healthy neurons, is a major finding in demented Alzheimer's disease (AD) patients. However, the association of autophagy with maintenance of cognitive integrity in resilient individuals who have AD neuropathology but remain non-demented (NDAN) has not been evaluated. METHODS: Using post mortem brain samples from age-matched healthy control, AD, and NDAN subjects, we evaluated autophagy in relation to Tau pathology using Western blot, immunofluorescence and RNA-seq. RESULTS: Compared to AD patients, NDAN subjects had preserved autophagy and reduced tauopathy. Furthermore, expression of autophagy genes and AD-related proteins were significantly associated in NDAN compared to AD and control subjects. DISCUSSION: Our results suggest preserved autophagy is a protective mechanism that maintains cognitive integrity in NDAN individuals. This novel observation supports the potential of autophagy-inducing strategies in AD therapeutics. Highlights: NDAN subjects have preserved autophagic protein levels comparable with control subjects. Compared to control subjects, NDAN subjects have significantly reduced Tau oligomers and PHF Tau phosphorylation at synapses that negatively correlate with autophagy markers. Transcription of autophagy genes strongly associates with AD-related proteins in NDAN donors.
KW - Alzheimer's disease
KW - autophagy
KW - resilience
KW - Tau
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U2 - 10.1002/alz.13074
DO - 10.1002/alz.13074
M3 - Article
C2 - 37191183
AN - SCOPUS:85159374506
SN - 1552-5260
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
ER -