Microtubule (MT) dysfunction, neurotoxicity, chromosome mis-segregation, and defective neuronal plasticity are all induced by A? peptide and implicated in Alzheimer's disease (AD) pathogenesis. Our recent data support the unifying hypothesis that A?-induced pathologies are caused in part by A? inhibiting specific MT motors, and we propose to test this hypothesis and its implications. Microtubules serve as the highways upon which ATP driven motor proteins move key cellular components such as proteins, vesicles, chromosomes and large macromolecules, including microtubules themselves, from one part of the cell to another. Many neurodegenerative diseases show defects in the microtubule transport system, underlining its importance in normal cellular physiology. Previously, we found that in AD patients, tg mice, and cultured cells, mutant amyloid precursor protein and presenilin genes that cause familial AD induce chromosome mis-segregation and aneuploidy, processes that are intimately involved with microtubule function. Confirmatory results from other labs showed that 30% of neurons in early AD cortex are aneuploid/ hyperdiploid. Recently, we found that after addition to human cells or Xenopus egg extracts, A? impairs the formation and stability of mitotic spindles and directly inhibits three microtubule motor kinesins, Eg5, KIF4A and MCAK, which are essential for the normal structure and function of the mitotic spindle, and, remarkably, are also present in neurons. In particular, Eg5 has severely reduced activity in extracts from brains of the APP/PS transgenic mice, a model of Alzheimer's disease, is inhibited in neurons treated with A?, and harbors polymorphisms that increase AD risk. Chemical inhibition of Eg5 results in mitotic defects, mis-localization of the NMDA receptor away from the plasma membrane, and inhibition of LTP. A?snegative impacton LTP, together with our new data regarding its influence on microtubule function, suggests that A? inhibition of memory processes in AD may derive in part from its inhibition of specific kinesins, which can disrupt both neurogenesis and neuroplasticity. By determining the effects of exposing cells, mouse brain slice cultures, and adult mice to chemical inhibitors of Eg5 and/or to A? on 1. Neurotoxicity, 2. LTP in slice cultures, and 3. learning and memory and AD-like neuropathology in adult mice, the proposed experiments will allow us to conclude whether or not the ability of the Alzheimer A? peptide to inhibit certain microtubule motors contributes importantly to its disruption of neurogenesis and neuronal function in Alzheimer's disease and whether such motor inhibition constitutes a novel target for AD therapy.

Public Health Relevance

Many human neurodegenerative diseases show abnormalities in the intracellular (microtubule) transport network. We hypothesize and have evidence that in Alzheimer's disease, the A? peptide inhibits a transport (motor) protein that moves cargo along the microtubule network. This, in turn results in defects in cell division necessary to generate new neurons and in localization of the neuron's receptors for important signaling molecules. Both of these defects would lead to decline in memory and cognition. In order to identify the best means for developing therapies for neurodegenerative diseases, we propose to determine whether these defects are, in fact caused by A? inhibition of a microtubule motor and if this results in learning and memory defects in a mouse model of Alzheimer's disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1-BDCN-Y (02))
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Corriveau, Roderick A
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University of Colorado Denver
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Potter, Huntington; Granic, Antoneta; Caneus, Julbert (2016) Role of Trisomy 21 Mosaicism in Sporadic and Familial Alzheimer's Disease. Curr Alzheimer Res 13:7-17
Freund, Ronald K; Gibson, Emily S; Potter, Huntington et al. (2016) Inhibition of the Motor Protein Eg5/Kinesin-5 in Amyloid β-Mediated Impairment of Hippocampal Long-Term Potentiation and Dendritic Spine Loss. Mol Pharmacol 89:552-9
Ari, Csilla; Borysov, Sergiy I; Wu, Jiashin et al. (2014) Alzheimer amyloid beta inhibition of Eg5/kinesin 5 reduces neurotrophin and/or transmitter receptor function. Neurobiol Aging 35:1839-49