Truncated and modified amyloid-beta species.

Markus P Kummer,Michael T Heneka

doi:10.1186/alzrt258

Abstract

Alzheimer’s disease pathology is closely connected to the processing of the amyloid precursor protein (APP) resulting in the formation of a variety of amyloid-beta (Aβ) peptides. They are found as insoluble aggregates in senile plaques, the histopathological hallmark of the disease. These peptides are also found in soluble, mostly monomeric and dimeric, forms in the interstitial and cerebrospinal fluid. Due to the combination of several enzymatic activities during APP processing, Aβ peptides exist in multiple isoforms possessing different N-termini and C-termini. These peptides include, to a certain extent, part of the juxtamembrane and transmembrane domain of APP. Besides differences in size, post-translational modifications of Aβ – including oxidation, phosphorylation, nitration, racemization, isomerization, pyroglutamylation, and glycosylation – generate a plethora of peptides with different physiological and pathological properties that may modulate disease progression.

Highlights

Since its identification from senile plaques, amyloid-beta (Aβ) peptide has been considered to play a central role in the pathology of Alzheimer’s disease (AD) [1]
Aβ is thought to accumulate in AD cases because of an imbalance in the production and clearance of this peptide resulting in the formation of the characteristic amyloid plaques in specific brain regions
The large majority of AD cases are of sporadic nature, showing inefficient removal of Aβ [2], whereas a minority of cases is caused by genetic mutations with an onset typically below age 65 years

Summary

Introduction

Since its identification from senile plaques, amyloid-beta (Aβ) peptide has been considered to play a central role in the pathology of Alzheimer’s disease (AD) [1]. The first cleavage occurs at a luminal, juxtamembrane position, resulting in the formation of a membrane-bound C-terminal stub that, in a subsequent step, is cleaved by an unconventional protease complex, called γ-secretase, within the transmembrane domain, thereby liberating Aβ. Both cleavages have been shown to be imprecise. The majority of APP molecules in non-neuronal cells are initially cleaved by α-secretase between positions 16 and 17 of the Aβ domain This is the so-called non-amyloidogenic pathway since the cleavage occurs within the Aβ domain, thereby preventing the production of Aβ. Inhibitors for glutaminyl cyclase [66], the relevant kinases for the phosphorylation of Aβ and NO-producing enzymes, especially NOS2 [55], should be tested as a therapeutic option

Conclusion

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