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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