The amyloid-? degradation intermediate A?34 is pericyte-associated and reduced in brain capillaries of patients with Alzheimer's disease.

ABSTRACT: An impairment of amyloid ?-peptide (A?) clearance is suggested to play a key role in the pathogenesis of sporadic Alzheimer's disease (AD). Amyloid degradation is mediated by various mechanisms including fragmentation by enzymes like neprilysin, matrix metalloproteinases (MMPs) and a recently identified amyloidolytic activity of ?-site amyloid precursor protein cleaving enzyme 1 (BACE1). BACE1 cleavage of A?40 and A?42 results in the formation of a common A?34 intermediate which was found elevated in cerebrospinal fluid levels of patients at the earliest disease stages. To further investigate the role of A?34 as a marker for amyloid clearance in AD, we performed a systematic and comprehensive analysis of A?34 immunoreactivity in hippocampal and cortical post-mortem brain tissue from AD patients and non-demented elderly individuals. In early Braak stages, A?34 was predominantly detectable in a subset of brain capillaries associated with pericytes, while in later disease stages, in clinically diagnosed AD, this pericyte-associated A?34 immunoreactivity was largely lost. A?34 was also detected in isolated human cortical microvessels associated with brain pericytes and its levels correlated with A?40, but not with A?42 levels. Moreover, a significantly decreased A?34/A?40 ratio was observed in microvessels from AD patients in comparison to non-demented controls suggesting a reduced proteolytic degradation of A?40 to A?34 in AD. In line with the hypothesis that pericytes at the neurovascular unit are major producers of A?34, biochemical studies in cultured human primary pericytes revealed a time and dose dependent increase of A?34 levels upon treatment with recombinant A?40 peptides while A?34 production was impaired when A?40 uptake was reduced or BACE1 activity was inhibited. Collectively, our findings indicate that A?34 is generated by a novel BACE1-mediated A? clearance pathway in pericytes of brain capillaries. As amyloid clearance is significantly reduced in AD, impairment of this pathway might be a major driver of the pathogenesis in sporadic AD.

SUBMITTER: Kirabali T 

PROVIDER: S-EPMC6892233 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature