Production of Amyloid-β in the Aβ-Protein-Precursor Proteolytic Pathway Is Discontinued or Severely Suppressed in Alzheimer’s Disease-Affected Neurons: Contesting the ‘Obvious’

Genes, Journal Year: 2025, Volume and Issue: 16(1), P. 46 - 46

Published: Jan. 2, 2025

A notion of the continuous production amyloid-β (Aβ) via proteolysis Aβ-protein-precursor (AβPP) in Alzheimer's disease (AD)-affected neurons constitutes both a cornerstone and an article faith research field. The present Perspective challenges this assumption. It analyses relevant empirical data reaches unexpected conclusion, namely that AD-afflicted neurons, AβPP-derived Aβ is either discontinued or severely suppressed, concept that, if proven, would fundamentally change our understanding disease. This suppression, effectively self-suppression, occurs context global inhibition cellular cap-dependent protein synthesis as consequence neuronal integrated stress response (ISR) elicited by intraneuronal (iAβ; hence self-suppression) upon reaching certain levels. Concurrently with suppression AβPP proteolytic pathway, ISR activates human but not mouse powerful AD-driving pathway generating C99 fragment independently AβPP. study describes molecular mechanisms potentially involved these phenomena, propounds novel approaches to generate transgenic animal models AD, advocates for utilization cells-based disease, makes verifiable predictions, suggests experiments designed validate proposed concept, considers its potential therapeutic implications. Remarkably, it opens up possibility conventional AβPP, BACE enzymes, γ-secretase components also suppressed under conditions AD-affected resulting dyshomeostasis follows whereas AD triggered iAβ accumulated ISR-eliciting levels, unconventional (triggered stressors distinct from iAβ) forms, driven (or only) produced AβPP-independent we previously, mainly, possibly exclusively, generated cleaved at γ-site due ISR-caused deficiency (apparently, "substance X" predicted previous study), paradigm consistent dictum George Perry "central causative" AD. strategies only deplete driver abrogate reverse ameliorate dyshomeostasis, significant contributor pathology.

Language: Английский

Quintessential Synergy: Concurrent Transient Administration of Integrated Stress Response Inhibitors and BACE1 and/or BACE2 Activators as the Optimal Therapeutic Strategy for Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(18), P. 9913 - 9913

Published: Sept. 13, 2024

The present study analyzes two potential therapeutic approaches for Alzheimer's disease (AD). One is the suppression of neuronal integrated stress response (ISR). Another targeted degradation intraneuronal amyloid-beta (

Language: Английский