Activation of the amyloid cascade in apolipoprotein e4 transgenic mice induces lysosomal activation and neurodegeneration resulting in marked cognitive deficits.

Activation of the amyloid cascade in apolipoprotein e4 transgenic mice induces lysosomal activation and neurodegeneration resulting in marked cognitive deficits. Research Abstract Details 

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Activation of the amyloid cascade in apolipoprotein e4 transgenic mice induces lysosomal activation and neurodegeneration resulting in marked cognitive deficits. Abstract Text:

The allele E4 of apolipoprotein E (apoE4), the most prevalent genetic risk factor for Alzheimer's disease, is associated histopathologically with elevated levels of brain amyloid. This led to the suggestion that the pathological effects of apoE4 are mediated by cross-talk interactions with amyloid beta peptide (Abeta), which accentuate the pathological effects of the amyloid cascade. The mechanisms underlying the Abeta-mediated pathological effects of apoE4 are unknown. We have shown recently that inhibition of the Abeta-degrading enzyme neprilysin in brains of wild-type apoE3 and apoE4 mice results in rapid and similar elevations in their total brain Abeta levels. However, the nucleation and aggregation of Abeta in these mice were markedly affected by the apoE genotype and were specifically enhanced in the apoE4 mice. We presently used the neprilysin inhibition paradigm to analyze the neuropathological and cognitive effects that are induced by apoE4 after activation of the amyloid cascade. This revealed that apoE4 stimulates isoform specifically the degeneration of hippocampal CA1 neurons and of entorhinal and septal neurons, which is accompanied by the accumulation of intracellular Abeta and apoE and with lysosomal activation. Furthermore, these neuropathological effects are associated isoform specifically with the occurrence of pronounced cognitive deficits in the ApoE4 mice. These findings provide the first in vivo evidence regarding the cellular mechanisms underlying the pathological cross talk between apoE4 and Abeta, as well as a novel model system of neurodegeneration in vivo that is uniquely suitable for studying the early stages of the amyloid cascade and the effects thereon of apoE4.

Activation of the amyloid cascade in apolipoprotein e4 transgenic mice induces lysosomal activation and neurodegeneration resulting in marked cognitive deficits. Publishing Authors By Initials

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Activation of the amyloid cascade in apolipoprotein e4 transgenic mice induces lysosomal activation and neurodegeneration resulting in marked cognitive deficits. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: The Journal of neuroscience : the official journal

VOLUME: 28

Page Numbers: 4690-701

Journal Abbreviation: J. Neurosci.

ISSN: 1529-2401

DAY: 30

MONTH: Apr

YEAR: 2008

Activation of the amyloid cascade in apolipoprotein e4 transgenic mice induces lysosomal activation and neurodegeneration resulting in marked cognitive deficits. Information

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LANGUAGE: eng

NlmUniqueID: 8102140

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Grant and Affiliation Information for Activation of the amyloid cascade in apolipoprotein e4 transgenic mice induces lysosomal activation and neurodegeneration resulting in marked cognitive deficits.

AFFILIATION: Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel, and Departments of Neurosciences and Pathology, University of California, San Diego, La Jolla, California 92093-0624.

Country: United States

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MEDLINETA: J Neurosci

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