Mechanisms of A beta mediated neurodegeneration in Alzheimer's disease.
Development of a comprehensive therapeutic treatment for the neurodegenerative Alzheimer's disease (AD) is limited by our understanding of the underlying biochemical mechanisms that drive neuronal failure. Numerous dysfunctional mechanisms have been described in AD, ranging from protein aggregation and oxidative stress to biometal dyshomeostasis and mitochondrial failure. In this review we discuss the critical role of amyloid-beta (A beta) in some of these potential mechanisms of neurodegeneration. The 39-43 amino acid A beta peptide has attracted intense research focus since it was identified as a major constituent of the amyloid deposits that characterise the AD brain, and it is now widely recognised as central to the development of AD. Familial forms of AD involve mutations that lead directly to altered A beta production from the amyloid-beta A4 precursor protein, and the degree of AD severity correlates with specific pools of A beta within the brain. A beta contributes directly to oxidative stress, mitochondrial dysfunction, impaired synaptic transmission, the disruption of membrane integrity, and impaired axonal transport. Further study of the mechanisms of A beta mediated neurodegeneration will considerably improve our understanding of AD, and may provide fundamental insights needed for the development of more effective therapeutic strategies.
Crouch
Peter J
PJ
Department of Pathology, The University of Melbourne, Victoria 3010, Australia. pjcrouch@unimelb.edu.au
Harding
Susan-Marie E
SM
White
Anthony R
AR
Camakaris
James
J
Bush
Ashley I
AI
Masters
Colin L
CL
D000544:Alzheimer Disease / Q000209:etiology / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000009:adverse effects / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001370:Axonal Transport / Q000502:physiology; D002463:Cell Membrane Permeability / Q000502:physiology; D019281:Dimerization; D006801:Humans; D008928:Mitochondria / Q000473:pathology; D008954:Models, Biological; D009410:Nerve Degeneration / Q000209:etiology*; D018384:Oxidative Stress / Q000502:physiology; D011499:Protein Processing, Post-Translational; D009435:Synaptic Transmission / Q000502:physiology