The 28‐amino acid form of an APLP1‐derived Aβ‐like peptide is a surrogate marker for Aβ42 production in the central nervous system

Abstract

Surrogate markers for the Alzheimer disease (AD)-associated 42-amino acid form of amyloid-β (Aβ42) have been sought because they may aid in the diagnosis of AD and for clarification of disease pathogenesis. Here, we demonstrate that human cerebrospinal fluid (CSF) contains three APLP1-derived Aβ-like peptides (APL1β) that are generated by β- and γ-cleavages at a concentration of ∼4.5 nM. These novel peptides, APL1β25, APL1β27 and APL1β28, were not deposited in AD brains. Interestingly, most γ-secretase modulators (GSMs) and familial AD-associated presenilin1 mutants that up-regulate the relative production of Aβ42 cause a parallel increase in the production of APL1β28 in cultured cells. Moreover, in CSF from patients with pathological mutations in presenilin1 gene, the relative APL1β28 levels are higher than in non-AD controls, while the relative Aβ42 levels are unchanged or lower. Most strikingly, the relative APL1β28 levels are higher in CSF from sporadic AD patients (regardless of whether they are at mild cognitive impairment or AD stage), than those of non-AD controls. Based on these results, we propose the relative level of APL1β28 in the CSF as a candidate surrogate marker for the relative level of Aβ42 production in the brain.

Second Generation γ-Secretase Modulators Exhibit Different Modulation of Notch β and Aβ Production

“…However, the biological relevance of the A␤-like peptides is currently unclear. However, the APP-like protein 1 A␤-like peptide, which is less amyloidogenic than A␤42, is present in human cerebrospinal fluid and is purported to function as a surrogate marker for A␤42 in response to ␥-secretase-targeting drugs (46). Thus, the selectivity pattern of a given GSM should be a major consideration in biomarker development.…”

Presenilins and -Secretase: Structure, Function, and Role in Alzheimer Disease

“…The biochemical evidence that the APP and its close relatives, amyloid precursor-like protein (APLP)-1 and -2 are substrates of g-secretase in vivo is also beyond discussion (De Strooper et al 1998;Naruse et al 1998;Scheinfeld et al 2002;Eggert et al 2004;Yanagida et al 2009). As described in Müller and Zheng (2011), APP-deficient animals have yielded little direct information with regard to the specific molecular pathways for which APP is required, and it therefore remains unclear to what extent g-secretase processing of APP (apart from generating the infamous Ab peptide) has biological consequences.…”

Relative Ratio and Level of Amyloid-β 42 Surrogate in Cerebrospinal Fluid of Familial Alzheimer Disease Patients with Presenilin 1 Mutations

“…CSF samples of 4 FAD patients with a PS1 mutation (PS1 L85P, L286V, L381V and G206V; PS1-FAD patients) and 22 neurological control patients (controls) were used (table 1) [12]. CSF samples of the 2 other FAD patients with a PS1 mutation (PS1 H163R and M233L) were excluded from this study, because these two mutations do not affect γ-cleavage of amyloid precursor-like protein 1 [12].…”

“…CSF samples of the 2 other FAD patients with a PS1 mutation (PS1 H163R and M233L) were excluded from this study, because these two mutations do not affect γ-cleavage of amyloid precursor-like protein 1 [12]. …”

“…The relative ratio of CSF APL1β28 to total APL1β (the APL1β28 ratio) is higher in PS1-FAD cases than in non-AD cases [12]. In this study, we analyzed CSF APL1β levels, including those of APL1β28, in PS1-FAD patients and in neurological control patients and tried to estimate whether the absolute values of newly generated Aβ42 levels are comparatively elevated in the brains of the PS1-FAD patients.…”