Amyloid-independent mechanisms in Alzheimer's disease pathogenesis

• Published in: The Journal of neuroscience Vol. 30; no. 45; pp. 14946 - 14954
• Main Authors: Pimplikar, Sanjay W, Nixon, Ralph A, Robakis, Nikolaos K, Shen, Jie, Tsai, Li-Huei
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 10.11.2010
• Series: Mini-Symposium
• Subjects: Alzheimer Disease - etiology; Alzheimer Disease - pathology; Amyloid beta-Peptides; Humans; Lysosomes - pathology; Neurons - pathology; Protein Transport; Signal Transduction; Symposium and Mini-Symposium
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.4305-10.2010

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.