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J Neurosci. 2010 Nov 10;30(45):14946-54. doi: 10.1523/JNEUROSCI.4305-10.2010.

Amyloid-independent mechanisms in Alzheimer's disease pathogenesis.

Author information

1
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

Abstract

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.

PMID:
21068297
PMCID:
PMC3426835
DOI:
10.1523/JNEUROSCI.4305-10.2010
[Indexed for MEDLINE]
Free PMC Article
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