Protein homeostasis gene dysregulation in pretangle-bearing nucleus basalis neurons during the progression of Alzheimer’s disease

• Published in: Neurobiology of aging 2016-06, Vol.42, p.80-90
• Main Authors: Tiernan, Chelsea T, Ginsberg, Stephen D, Guillozet-Bongaarts, Angela L, Ward, Sarah M, He, Bin, Kanaan, Nicholas M, Mufson, Elliott J, Binder, Lester I, Counts, Scott E
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer's disease; Basal Nucleus of Meynert - metabolism; Basal Nucleus of Meynert - pathology; Cell Survival - genetics; Cholinergic basal forebrain; Cognitive Dysfunction - genetics; Cognitive Dysfunction - pathology; Disease Progression; Female; Gene Expression - genetics; Homeostasis - genetics; Humans; Internal Medicine; Male; Mild cognitive impairment; Nerve Tissue Proteins - metabolism; Neurofibrillary Tangles - metabolism; Neurofibrillary Tangles - pathology; Neurology; Neurons - metabolism; Neurons - pathology; Phosphorylation; Protein homeostasis; Proteolysis; Tau; tau Proteins - metabolism; Up-Regulation
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2016.02.031

Abstract Conformational phosphorylation and cleavage events drive the tau protein from a soluble, monomeric state to a relatively insoluble, polymeric state that precipitates the formation of neurofibrillary tangles (NFTs) in projection neurons in Alzheimer’s disease (AD), including the magnocellular perikarya located in the nucleus basal of Meynert (NBM) complex of the basal forebrain. Whether these structural changes in the tau protein are associated with pathogenic changes at the molecular and cellular level remains undetermined during the onset of AD. Here we examined alterations in gene expression within individual NBM neurons immunostained for pS422, an early tau phosphorylation event, or dual labeled for pS422 and TauC3, a later stage tau neoepitope, from tissue obtained postmortem from subjects who died with an antemortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or mild/moderate AD. Specifically, pS422-positive pretangles displayed an upregulation of select gene transcripts subserving protein quality control. On the other hand, late stage TauC3-positive NFTs exhibited upregulation of mRNAs involved in protein degradation but also cell survival. Taken together, these results suggest that molecular pathways regulating protein homeostasis are altered during the evolution of NFT pathology in the NBM. These changes likely contribute to the disruption of protein turnover and neuronal survival of these vulnerable NBM neurons during the progression of AD.