The chaperones HSP90AA1, HSP90AB1 and BAG3 are specifically distributed among human hippocampal subfields during different Alzheimer's disease stages

Abstract

Alzheimer's disease (AD) includes amyloid-β plaques and tau tangles as associated proteinopathies. Tau aggregates appear in a sequential and predictable manner, defined by six stages (Braak stages I–VI) of neuropathological diagnosis, with the hippocampus, particularly the CA1 subfield, being involved in the early stages. Chaperones play a key role in amyloid-β and tau misfolding. Chaperones constitute a vast family of proteins, but proteomic assays have indicated that HSP90AA1, HSP90AB1 and BAG3 are differentially expressed in the hippocampus of human AD patients. However, it is unknown whether the distribution of these proteins changes across different hippocampal subfields and/or in different neuropathological stages. Therefore, the distributions of the HSP90AA1, HSP90AB1 and BAG3 chaperones across hippocampal subfields (CA1, CA2, CA3 and DG) and across neuropathological stages (non-AD, 0; initial-AD, I-I; intermediate-AD, III–IV; and advanced-AD, V–VI) were stereologically quantified using the Area Fraction Fractionator probe. The area fraction of HSP90AA1 was lower in CA1 in advanced stages, whereas that of HSP90AB1 was greater in CA2 in advanced stages. In contrast, the area fraction of BAG3 was greater in CA1, CA3 and the DG between the non-AD and initial-AD stages but was lower in the DG in the intermediate-AD stage. This finding suggests that chaperone dysregulation could be responsible for the altered clearance and increased pathological misfolding that is observed in AD, leading to differential subfield vulnerability. Indeed, these chaperones could be useful as predictive biomarkers or therapeutic targets for AD because of their differential distribution across subfields and stages, which may increase the sensitivity and specificity of these proteins for use in these ways.