Decrease in p3‐Alcβ37 and p3‐Alcβ40, products of Alcadein β generated by γ‐secretase cleavages, in aged monkeys and patients with Alzheimer's disease

Abstract

IntroductionNeuronal p3-Alcβ peptides are generated from the precursor protein Alcadein β (Alcβ) through cleavage by α- and γ-secretases of the amyloid β (Aβ) protein precursor (APP). To reveal whether p3-Alcβ is involved in Alzheimer's disease (AD) contributes for the development of novel therapy and/or drug targets.MethodsWe developed new sandwich enzyme-linked immunosorbent assay (sELISA) systems to quantitate levels of p3-Alcβ in the cerebrospinal fluid (CSF).ResultsIn monkeys, CSF p3-Alcβ decreases with age, and the aging is also accompanied by decreased brain expression of Alcβ. In humans, CSF p3-Alcβ levels decrease to a greater extent in those with AD than in age-matched controls. Subjects carrying presenilin gene mutations show a significantly lower CSF p3-Alcβ level. A cell study with an inverse modulator of γ-secretase remarkably reduces the generation of p3-Alcβ37 while increasing the production of Aβ42.DiscussionAging decreases the generation of p3-Alcβ, and further significant decrease of p3-Alcβ caused by aberrant γ-secretase activity may accelerate pathogenesis in AD.

Amyloidogenic processing of amyloid β protein precursor (APP) is enhanced in the brains of alcadein α–deficient mice

“…Contrary to the aforementioned expectation of X11 family members, Alcb deficiency did not augment amyloidogenic processing of APP, suggesting that Alcb has different functions. Our recent observations suggested that Alcb may be differently involved in AD pathogenesis in terms of p3-Alcb peptide generation (55), which would further support this notion. Alcb is also reported to have synaptogenic activity through association with a-neurexin; however, Alca does not exhibit such activity (56).…”

Brain p3‐Alcβ peptide restores neuronal viability impaired by Alzheimer's amyloid β‐peptide

“…Since endogenous p3-Alcb levels may be too low to protect neurons against the increased neurotoxic Abo burden in the brain of aged individuals, increasing p3-Alcb9-19 levels via peripheral administration has the potential to increase neuronal viability in aged individuals. Furthermore, our recent analysis shows that endogenous p3-Alcb levels in the CSF of AD patients are significantly lower than in age-matched nondemented subjects (Hata et al, 2019), which is more obvious in early AD patients (Fig 1). Elderly subjects with low levels of p3-Alcb are likely to experience the greater acceleration of AD pathology.…”

“…We previously reported that the p3-Alcb levels in CSF significantly reduced in patients who were clinically diagnosed with AD (Hata et al, 2019). To further investigate the relationship between AD progression and p3-Alcb levels, we examined p3-Alcb37 levels in CSF of patients who had been classified into AD biomarker categories (Jack et al, 2018).…”

“…We previously reported that endogenous p3-Alcb levels in CSF of monkeys decrease with age (Hata et al, 2019). We further analyzed age-related changes in brain p3-Alcb and Ab levels using the monkey brain (Fig EV5).…”

“…Among the p3-Alcs secreted, the major peptides p3-Alca35 (of Alca) and p3-Alcb37 (of Alcb) are found in human cerebrospinal fluid (CSF) at levels similar to that of Ab40 (Hata et al, 2009(Hata et al, , 2011. Moreover, the levels of p3-Alcb in CSF are notably reduced in AD (Hata et al, 2019). These lines of evidence suggest that p3-Alcb is closely associated with AD pathophysiology.…”