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

• Published in: Acta neuropathologica communications Vol. 7; no. 1
• Main Authors: Kirabali, Tunahan, Rigotti, Serena, Siccoli, Alessandro, Liebsch, Filip, Shobo, Adeola, Hock, Christoph, Nitsch, Roger M, Multhaup, Gerhard, Kulic, Luka
• Format: Journal Article
• Language: English
• Published: BioMed Central Ltd 03-12-2019
• Subjects: Advertising executives; Alzheimer's disease; Amyloid beta-protein; Analysis; Brain; Elderly; Enzymes; Medical research; Novels; Peptides; Proteolysis
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-019-0846-8

An impairment of amyloid [beta]-peptide (A[beta]) 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 [beta]-site amyloid precursor protein cleaving enzyme 1 (BACE1). BACE1 cleavage of A[beta]40 and A[beta]42 results in the formation of a common A[beta]34 intermediate which was found elevated in cerebrospinal fluid levels of patients at the earliest disease stages. To further investigate the role of A[beta]34 as a marker for amyloid clearance in AD, we performed a systematic and comprehensive analysis of A[beta]34 immunoreactivity in hippocampal and cortical post-mortem brain tissue from AD patients and non-demented elderly individuals. In early Braak stages, A[beta]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[beta]34 immunoreactivity was largely lost. A[beta]34 was also detected in isolated human cortical microvessels associated with brain pericytes and its levels correlated with A[beta]40, but not with A[beta]42 levels. Moreover, a significantly decreased A[beta]34/A[beta]40 ratio was observed in microvessels from AD patients in comparison to non-demented controls suggesting a reduced proteolytic degradation of A[beta]40 to A[beta]34 in AD. In line with the hypothesis that pericytes at the neurovascular unit are major producers of A[beta]34, biochemical studies in cultured human primary pericytes revealed a time and dose dependent increase of A[beta]34 levels upon treatment with recombinant A[beta]40 peptides while A[beta]34 production was impaired when A[beta]40 uptake was reduced or BACE1 activity was inhibited. Collectively, our findings indicate that A[beta]34 is generated by a novel BACE1-mediated A[beta] 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. Keywords: Alzheimer's disease, Pericyte, A[beta]34, Amyloid clearance