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

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.

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

“…Neuropsychological and clinical examinations, as well as postmortem diagnostic evaluations, have been described elsewhere 46 . Demographic, antemortem cognitive testing, and postmortem diagnostic variables were compared among the groups using the nonparametric Kruskal-Wallis Test with Bonferroni correction for multiple comparisons.…”

Pretangle pathology within cholinergic nucleus basalis neurons coincides with neurotrophic and neurotransmitter receptor gene dysregulation during the progression of Alzheimer's disease

“…Tissue samples were obtained and processed as previously published (Counts et al, 2006; Mufson et al, 1999; Tiernan et al, 2016b). At autopsy, the cerebrum was slabbed into 1 cm sections and one hemisphere was immersion-fixed in 4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.2 for 24–72 h at 4 °C followed by cryoprotection; the opposite hemisphere was snap frozen.…”

“…Immunohistochemistry to identify pS422- and TauC3-immunopositive neurons in the anteromedial nbM subfields has been detailed previously (Tiernan et al, 2016b). Briefly, the presence of intact RNA was confirmed in each case by acridine orange histofluorescence (Ginsberg et al, 1997).…”

“…In contrast, we observed that Ngfr transcripts (encoding p75 NTR ) remain steady throughout clinical disease progression (Ginsberg et al, 2006); however, a phenotypic silencing of p75 NTR immunoreactivity is observed in nbM neurons of MCI and AD subjects (Mufson et al, 2002b). While the expression patterns of these AChR and neurotrophin receptor mRNAs appears to follow clinical disease progression, recent work from our group suggests that specific stages of tau pathology and not clinical disease status drive differential gene regulation in nbM neurons (Tiernan et al, 2016b). …”

“…Cholinergic nbM neurons regulate memory and attention (Baxter and Chiba, 1999) and undergo progressive degeneration in Alzheimer’s disease (AD) that correlates with disease progression and degree of cognitive impairment (Bierer et al, 1995). Recent work from our group suggests that the cascade of pathophysiological events leading to cholinergic nbM neuronal degeneration in AD is associated with the appearance of discrete epitopes within the microtubule-associated protein tau (Tiernan et al, 2016b), which are progressively revealed as this protein undergoes a pathological sequence of post-translational modifications precipitating the formation of neurofibrillary tangles (NFTs) in AD (Braak et al, 1994; García-Sierra et al, 2003; Ghoshal et al, 2002; Ghoshal et al, 2001; Guillozet-Bongaarts et al, 2005). …”