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• W2033268093 abstract "Alzheimer's Disease (AD) currently affects 5 million Americans, a number predicted to triple by 2050. Earlier, effective treatments are necessary to prevent AD from becoming a public health crisis; creating such therapies will require a thorough understanding of the initial mechanisms of disease pathology. The pathological signature of AD is amyloid plaques primarily composed of insoluble aggregates of the amyloid beta fragment (Aβ). A growing body of evidence suggests that soluble Aβ aggregates precede plaque formation, and it may be these oligomeric intermediates that are responsible for early symptoms of AD. We have previously shown the protein phosphatase calcineurin (CaN) negatively regulates synaptic plasticity, and mediates some of the early dysfunction induced by Aβ in a transgenic model of AD. This occurs prior to amyloid plaque deposition, implicating an aggregated Aβ species formed before fibrillar plaques. Such an oligomeric species is detectable in young transgenic mice, coincidental with the onset of behavioral deficits. In vitro, in vivo, and ex vivo experiments were designed to characterize the potential of soluble, oligomeric and fibrillar Aβ to induce cell death, oppose LTP and promote memory deficits through CaN induction. In SY5Y cells, only oligomeric Aβ stimulated CaN activity and induced marked cell death. Both outcomes were preventable by treatment with an amyloid oligomer-specific antibody. Cell death was also prevented by CaN inhibitor FK506, but not by control drug rapamycin. Only cells treated with oligomers displayed reduced active CREB – a transcription factor important for memory function which is negatively regulated by CaN via dephosphorylation. CaN also targets the pro-apoptotic protein Bad, the dephosphorylation promotes apoptosis. We measured decreasing levels of pBad with increasing concentrations of oligomeric Aβ. Ex vivo patch clamp recordings of brain slices incubated with oligomeric Aβ indicated that this specific conformation opposes LTP in a CaN dependent fashion. In vivo, acute intracerebroventricular injections of synthetic oligomeric Aβ induce CaN-dependent memory deficits in wild-type mice. Together, these data suggest that oligomeric Aβ stimulates aberrant CaN activity, providing a putative mechanism for the early memory deficits that precede the appearance of insoluble amyloid deposits and overt neuronal death." @default.
• W2033268093 created "2016-06-24" @default.
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• W2033268093 date "2008-07-01" @default.
• W2033268093 modified "2023-09-27" @default.
• W2033268093 title "P4-239: Selective induction of calcineurin activity and signaling by oligomeric amyloid-beta" @default.
• W2033268093 doi "https://doi.org/10.1016/j.jalz.2008.05.2307" @default.
• W2033268093 hasPublicationYear "2008" @default.
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