Understanding memory loss in Alzheimer's Disease

William Klein, PhD
Northwestern University (Evanston, IL)
Year Awarded:
2006
Grant Duration:
April 1, 2006 to March 31, 2009
Disease:
Alzheimer's Disease
Award Amount:
$300,000
Grant Reference ID:
A2006092
Award Type:
Standard
Award Region:
US Midwestern

Synaptic Attack by ADDLs: A Mechanism for Memory Loss

Summary

These experiments will examine how a class of molecules, ADDLs, detrimentally affect the structure of neurons.

Details


Memory formation begins at synapses, and it appears likely that destruction of memory formation is due to synapse failure. Our proposal investigates the molecular cause of this failure. It focuses on a new neurotoxin, called ADDLs, that was discovered and characterized by our group over the past several years. We previously showed that ADDLs accumulate in AD brains, so it is important to know how they act. Our most recent work established that ADDLs attack synapses, a fact that gives very strong support to the idea that AD is a synapse failure. We now want to discover what type of structural and molecular damage ADDLs cause to synapses after they bind. Our preliminary evidence strongly indicates that ADDLs rapidly change the geometry of synapses into a shape often seen in mental retardation. Our evidence also indicates that the neurotransmitter receptor molecules required for information storage are removed from synapses. We plan to verify and extend these preliminary results by new experiments using state-of-the-art experimental models to study synapse biology and the impact of ADDLs. Our experiments in the long run will determine how the ADDLs attack on synapses could result in the catastrophic memory failure suffered in early Alzheimer's disease.

Publications

Lacor PN, Buniel MC, Furlow PW, Sanz Clemente A, Velasco PT, Wood M, Viola KL, Klein WL. (2007) Abeta oligomer-induced aberrations in synapse composition, shape and density provide a molecular basis for loss of connectivity in Alzheimer's disease J Neurosci. 27(4), 796-807.  

Zhao W-Q, Lacor PN, Chen H, Lambert MP, Quon MJ, Krafft GA and Klein WL. (2009) Insulin receptor dysfunction impairs cellular clearance of neurotoxic oligomeric Abeta. J Biol. Chem. 284(28), 18742-18753.  

Tchantchou F, Lacor PN, Cao Z, Lao L, Hou Y, Cui C, Klein WL, Luo Y (2009). Stimulation of neurogensis and synaptogenesis by bilobalide and quercetin via common final pathway in hippocampal neurons. J Alzheimers Dis. 2009 Dec;18(4):787-98.  

Lacor PN, Buniel MC, Furlow P, Sanz Clemente A, Velasco P, Viola K, Klein WL. Abeta oligomers induce aberrations in dendritic spine shape and density by interfering with memantine-sensitive receptors: could oligomers be responsible for the loss of connectivity characteristic of Alzheimer's disease? 37th Annual meeting for Neuroscience (San Diego, Nov 2007). Abstract 484.19. [conference abstract]

De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP, Viola KL, Zhao WQ, Ferreira ST, Klein WL (2009) Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of ABeta oligomers. Proc Natl Acad Sci U S A. 106(6):1971-6.  

Lambert MP, Velasco PT, Viola KL, Klein WL. (2009) Targeting generation of antibodies specific to conformational epitopes of amyloid Beta-derived neurotoxins. CNS Neurol Disord Drug Targets. 8(1):65-81.  

Lacor PN. Advances on the understanding of the origins of synaptic pathology in AD. Hot Topics in Alzheimers Disease - Current genomics 2007, 8(8):486-508.  

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