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A?34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer's disease progression.

ABSTRACT: The beta-site APP cleaving enzyme 1 (BACE1) is known primarily for its initial cleavage of the amyloid precursor protein (APP), which ultimately leads to the generation of A? peptides. Here, we provide evidence that altered BACE1 levels and activity impact the degradation of A?40 and A?42 into a common A?34 intermediate. Using human cerebrospinal fluid (CSF) samples from the Amsterdam Dementia Cohort, we show that A?34 is elevated in individuals with mild cognitive impairment who later progressed to dementia. Furthermore, A?34 levels correlate with the overall A? clearance rates in amyloid positive individuals. Using CSF samples from the PREVENT-AD cohort (cognitively normal individuals at risk for Alzheimer's disease), we further demonstrate that the A?34/A?42 ratio, representing A? degradation and cortical deposition, associates with pre-clinical markers of neurodegeneration. We propose that A?34 represents a marker of amyloid clearance and may be helpful for the characterization of A? turnover in clinical samples.

SUBMITTER: Liebsch F

PROVIDER: S-EPMC6527709 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Aβ34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer's disease progression.

Liebsch Filip F Kulic Luka L Teunissen Charlotte C Shobo Adeola A Ulku Irem I Engelschalt Vivienne V Hancock Mark A MA van der Flier Wiesje M WM Kunach Peter P Rosa-Neto Pedro P Scheltens Philip P Poirier Judes J Saftig Paul P Bateman Randall J RJ Breitner John J Hock Christoph C Multhaup Gerhard G

Nature communications 20190520 1

The beta-site APP cleaving enzyme 1 (BACE1) is known primarily for its initial cleavage of the amyloid precursor protein (APP), which ultimately leads to the generation of Aβ peptides. Here, we provide evidence that altered BACE1 levels and activity impact the degradation of Aβ40 and Aβ42 into a common Aβ34 intermediate. Using human cerebrospinal fluid (CSF) samples from the Amsterdam Dementia Cohort, we show that Aβ34 is elevated in individuals with mild cognitive impairment who later progresse ...[more]

PMID: 31110178

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Project description: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.

Dataset Information

A?34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer's disease progression.

Publications

Aβ34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer's disease progression.

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