The Effects of Soluble Aβ Oligomers on Neurodegeneration in Alzheimer's Disease

Author(s): Jonathan Brouillette.

Journal Name: Current Pharmaceutical Design

Volume 20 , Issue 15 , 2014

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Abstract:

The neurodegenerative process that defines Alzheimer’'s disease (AD) is initially characterized by synaptic alterations followed by synapse loss and ultimately cell death. Decreased synaptic density that precedes neuronal death is the strongest pathological correlate of cognitive deficits observed in AD. Substantial synapse and neuron loss occur early in disease progression in the entorhinal cortex (EC) and the CA1 region of the hippocampus, when memory deficits become clinically detectable. Mounting evidence suggests that soluble amyloid-β  (Aβ) oligomers trigger synapse dysfunction both in vitro and in vivo. However, the neurodegenerative effect of Aβ species observed on neuronal culture or organotypic brain slice culture has been more challenging to mimic in animal models. While most of the transgenic mice that overexpress Aβ  show abundant amyloid plaque pathology and early synaptic alterations, these models have been less successful in recapitulating the spatiotemporal pattern of cell loss observed in AD. Recently we developed a novel animal model that revealed the neurodegenerative effect of soluble low-molecular-weight Aβ oligomers in vivo. This new approach may now serve to determine the molecular and cellular mechanisms linking soluble Aβ  species to neurodegeneration in animals. In light of the low efficiency of AD therapies based on the amyloid cascade hypothesis, a novel framework, the aging factor cascade hypothesis, is proposed in an attempt to integrate the new data and concepts that emerged from recent research to develop disease modifying therapies.

Keywords: Aβ oligomers, neurodegeneration, Alzheimer's disease, animal models, aging, hippocampus, aging factor cascade hypothesis, memory deficits, synaptic dysfunction, tau.

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Article Details

VOLUME: 20
ISSUE: 15
Year: 2014
Page: [2506 - 2519]
Pages: 14
DOI: 10.2174/13816128113199990498
Price: $58

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