title: The effects of soluble Aβ oligomers on neurodegeneration in Alzheimer's disease.
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.
authors.affiliation: Yale University, School of Medicine, 230 South Frontage Road, SHM I room 269, New Haven, CT 06519 USA. jonathan.brouillette@yale.edu.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Brouillette
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D009410:Nerve Degeneration; D055503:Protein Multimerization
chemical_list: D016229:Amyloid beta-Peptides