Cortical pyroglutamate amyloid-β levels and cognitive decline in Alzheimer's disease
Posterior cingulate cortex (PCC) accumulates amyloid-β (Aβ) early in Alzheimer's disease (AD). The relative concentrations of full-length Aβ and truncated, pyroglutamate-modified Aβ (NpE3) forms, and their correlations to cognitive dysfunction in AD, are unknown. We quantified AβNpE3-42, AβNpE3-40, Aβ1-42, and Aβ1-40 concentrations in soluble (nonfibrillar) and insoluble (fibrillar) pools in PCC from subjects with an antemortem clinical diagnosis of no cognitive impairment, mild cognitive impairment, or mild-moderate AD. In clinical AD, increased PCC concentrations of Aβ were observed for all Aβ forms in the insoluble pool but only for Aβ1-42 in the soluble pool. Lower Mini-Mental State Exam and episodic memory scores correlated most strongly with higher concentrations of soluble and insoluble Aβ1-42. Greater neuropathology severity by Consortium to Establish a Registry for Alzheimer's Disease and National Institute on Aging-Reagan pathologic criteria was associated with higher concentrations of all measured Aβ forms, except soluble AβNpE3-40. Low concentrations of soluble pyroglutamate Aβ across clinical groups likely reflect its rapid sequestration into plaques, thus, the conversion to fibrillar Aβ may be a therapeutic target.
Alzheimer's disease, Amyloid-β, Episodic memory, MCI, Posterior cingulate cortex, Pyroglutamate-modified Aβ
Neurobiology of Aging
Digital Object Identifier (DOI)
Pivtoraiko, Violetta N.; Abrahamson, Eric E.; Leurgans, Sue E.; DeKosky, Steven T.; Mufson, Elliott J.; and Ikonomovic, Milos D., "Cortical pyroglutamate amyloid-β levels and cognitive decline in Alzheimer's disease" (2015). Translational Neuroscience. 1769.