Amyloid-independent mechanisms in Alzheimer's disease pathogenesis.
Despite the progress of the past two decades, the cause of Alzheimer's disease (AD) and effective treatments against it remain elusive. The hypothesis that amyloid-β (Aβ) peptides are the primary causative agents of AD retains significant support among researchers. Nonetheless, a growing body of evidence shows that Aβ peptides are unlikely to be the sole factor in AD etiology. Evidence that Aβ/amyloid-independent factors, including the actions of AD-related genes, also contribute significantly to AD pathogenesis was presented in a symposium at the 2010 Annual Meeting of the Society for Neuroscience. Here we summarize the studies showing how amyloid-independent mechanisms cause defective endo-lysosomal trafficking, altered intracellular signaling cascades, or impaired neurotransmitter release and contribute to synaptic dysfunction and/or neurodegeneration, leading to dementia in AD. A view of AD pathogenesis that encompasses both the amyloid-dependent and -independent mechanisms will help fill the gaps in our knowledge and reconcile the findings that cannot be explained solely by the amyloid hypothesis.
Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, USA. pimplis@ccf.org
Sanjay W
SW
Pimplikar
Ralph A
RA
Nixon
Nikolaos K
NK
Robakis
Jie
J
Shen
Li-Huei
LH
Tsai
D000544:Alzheimer Disease / Q000209:etiology* / Q000473:pathology; D016229:Amyloid beta-Peptides; D006801:Humans; D008247:Lysosomes / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D021381:Protein Transport; D015398:Signal Transduction
D016229:Amyloid beta-Peptides