A\u03b234 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer\u2019s disease progression

Filip Liebsch,Christoph Hock,Gerhard Multhaup,Charlotte Teunissen,Peter Kunach,Philip Scheltens,Irem Ulku,John Breitner,Wiesje M Van Der Flier,Paul Saftig,Luka Kulic,Randall J Bateman,Pedro Rosa-Neto,Adeola Shobo,Mark A Hancock,Judes Poirier,Vivienne Engelschalt

doi:10.1038/s41467-019-10152-w

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 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 progressed to dementia. Furthermore, Aβ34 levels correlate with the overall Aβ 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 Aβ34/Aβ42 ratio, representing Aβ degradation and cortical deposition, associates with pre-clinical markers of neurodegeneration. We propose that Aβ34 represents a marker of amyloid clearance and may be helpful for the characterization of Aβ turnover in clinical samples.

Highlights

The beta-site APP cleaving enzyme 1 (BACE1) is known primarily for its initial cleavage of the amyloid precursor protein (APP), which leads to the generation of Aβ peptides
Since we have previously shown that Aβ34 is a common intermediate in the enzymatic processing of two distinct Aβ degradation pathways[6], the present study examines the levels and metabolism of Aβ34 in the brains of BACE1-deficient mice, in brain and cerebrospinal fluid (CSF) of rats treated with a BACE1-specific inhibitor, a cultured human neuronal cell line (SH-SY5Y), and CSF samples from individuals at various clinical stages of Alzheimer’s disease (AD)
BACE1−/− mice had significantly elevated levels of cerebral APP and/or soluble APP compared with their BACE1+/− and wild-type littermates, whereas there was no significant difference between BACE1+/− and wild-type animals (Fig. 1a, c)

Summary

Introduction

The beta-site APP cleaving enzyme 1 (BACE1) is known primarily for its initial cleavage of the amyloid precursor protein (APP), which leads to the generation of Aβ peptides. 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 progressed to dementia. Using CSF samples from the PREVENT-AD cohort (cognitively normal individuals at risk for Alzheimer’s disease), we further demonstrate that the Aβ34/Aβ42 ratio, representing Aβ degradation and cortical deposition, associates with pre-clinical markers of neurodegeneration. Excess BACE1 activity can lead to (i) alternative APP processing at the β’-site, generating metabolically labile Aβ11-X peptides[17], or (ii) Aβ degradation, by catalyzing the C-terminal truncation of Aβ40 and Aβ42 into non-amyloidogenic Aβ3418–21. The amyloidolytic roles of BACE1 in Aβ metabolism are currently not well defined, either in health (i.e., physiological homeostasis) or disease (i.e., AD pathogenesis)

Methods

Results

Conclusion