β-amyloid and the pathomechanisms of Alzheimer’s disease: A comprehensive view

Research output: Contribution to journalReview article

33 Citations (Scopus)

Abstract

Protein dyshomeostasis is the common mechanism of neurodegenerative diseases such as Alzheimer’s disease (AD). Aging is the key risk factor, as the capacity of the proteostasis network declines during aging. Different cellular stress conditions result in the up-regulation of the neurotrophic, neuroprotective amyloid precursor protein (APP). Enzymatic processing of APP may result in formation of toxic Aβ aggregates (β-amyloids). Protein folding is the basis of life and death. Intracellular Aβ affects the function of subcellular organelles by disturbing the endoplasmic reticulum-mitochondria cross-talk and causing severe Ca2+-dysregulation and lipid dyshomeostasis. The extensive and complex network of proteostasis declines during aging and is not able to maintain the balance between production and disposal of proteins. The effectivity of cellular pathways that safeguard cells against proteotoxic stress (molecular chaperones, aggresomes, the ubiquitin-proteasome system, autophagy) declines with age. Chronic cerebral hypoperfusion causes dysfunction of the blood-brain barrier (BBB), and thus the Aβ-clearance from brain-to-blood decreases. Microglia-mediated clearance of Aβ also declines, Aβ accumulates in the brain and causes neuroinflammation. Recognition of the above mentioned complex pathogenesis pathway resulted in novel drug targets in AD research.

Original languageEnglish
Article number1692
JournalMolecules
Volume22
Issue number10
DOIs
Publication statusPublished - Oct 2017

Keywords

  • APP
  • Alzheimer’s disease
  • Autophagy
  • Aβ-clearance
  • Ca2+ dysregulation
  • ER-mitochondrial axis
  • Intracellular Aβ
  • Lipid dyshomeostasis
  • Molecular chaperones
  • Neuroinflammation
  • Protein

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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