Cortical pyroglutamate amyloid-β levels and cognitive decline in Alzheimer's disease

Document Type

Article

Abstract

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.

Keywords

Alzheimer's disease, Amyloid-β, Episodic memory, MCI, Posterior cingulate cortex, Pyroglutamate-modified Aβ

Publication Date

1-1-2015

Publication Title

Neurobiology of Aging

ISSN

01974580

E-ISSN

15581497

Volume

36

Issue

1

First Page

12

Last Page

19

PubMed ID

25048160

Digital Object Identifier (DOI)

10.1016/j.neurobiolaging.2014.06.021

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