Preserved Autophagy in Cognitive Intact Non‐Demented Individuals with Alzheimer’s Neuropathology

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is a terminal neurodegenerative disease and the most common cause of dementia. Notably, some individuals, here referred to as Non‐Demented individuals with Alzheimer’s Neuropathology (NDAN) are cognitively intact despite the presence of neuropathology consistent with fully symptomatic AD and have decreased Tau oligomers at synapses. Growing evidence supports that dysfunctional autophagy, the primary cell mechanism responsible for removing protein aggregates and a route of clearance for Tau in healthy neurons, is a major finding in demented AD patients. However, the association of autophagy with maintenance of cognitive integrity in resilient individuals has not been evaluated. Thus, the understanding of the neuroprotective mechanisms to evade cognitive decline to preserve synaptic functional integrity is important for the development of therapeutic approaches to prevent dementia.MethodHere we evaluated autophagy as a key protective mechanism for maintenance of cognitive integrity in NDAN subjects by efficient removal of tau oligomers. Using postmortem hippocampal samples from age‐matched healthy controls (n = 6), AD (n = 7) and NDAN (n = 7) we performed immunofluorescence and comparative western blot analyses for regulatory molecules and ATGs (autophagy‐related genes) involved in autophagy. Tauopathy was accessed by the expression and phosphorylation levels at Ser202/Thr205 (AT8), Thr231 (AT180) and Ser396 (PHF13.6) of Tau oligomers.ResultWe found that NDAN subjects have significantly increased regulatory Beclin‐1, and Atg16L, Atg12, Atg3, Atg5, Atg7, LC3AB, and proteasomal PSMA5 but not lysosomal LAMP1 as compared to AD. Expression levels were comparable with healthy controls. Autophagic proteins, except p62, were negatively correlated to Tau oligomer (>65 kDa), but not to total Tau (>45 kDa), indicating autophagy being specific to tau oligomer clearance. Tau oligomer expression and levels of phosphorylation at Ser202/Thr205, Thr231, and Ser396 were significantly reduced in hippocampal tissue in NDAN as compared to AD, also confirmed by immunofluorescence analyses of Tau tangles.ConclusionOur results indicate, for the first time, intact autophagy and associated reduced tauopathy as one of protective mechanism in cognitive intact NDAN. This novel observation supports the potential of autophagy‐induced strategies in AD therapeutics