Neurotransmitter receptors in Alzheimer's disease

Ricardo Miledi, MD
Regents of the University of CA (Irvine, CA)
Year Awarded:
2006
Grant Duration:
April 1, 2006 to March 31, 2009
Disease:
Alzheimer's Disease
Award Amount:
$250,918
Grant Reference ID:
A2006054
Award Type:
Standard
Award Region:
US Southwestern

GABA and Glutamate receptors on Alzheimer's disease

Summary

Receptors from Alzheimer's brains will be compared with those from non-Alzheimer's brains, focusing on the receptors to GABA and Glutamate: the main inhibitory and excitatory neurotransmitters in the human brain. The effects of Amyloid beta will also be studied. This will help determine the cause of Alzheimer's disease and help to develop new treatments.

Details


All the functions of the brain, our sensations, memory etc. depend on the transmission of signals across the myriads of synapses that interconnect the billions of neurons of the brain. In the synaptic process neurotransmitter substances, released from one neuron, act on receptor proteins embedded in the membrane of neighboring neurons. Alzheimer's is a synaptic disease accompanied by neuronal loss. Nevertheless, very little is known about the neurotransmitter receptors of the Alzheimer's brain. We will study the structure and function of these receptors, using a method that we developed to micro-transplant receptors from the human brain to frog oocytes. Membranes, isolated from brains frozen post-mortem, are injected into oocytes. These membranes, carrying the original receptors from the Alzheimer's brain, and still embedded in their original membrane, fuse with the oocyte membrane. Remarkably, the receptors are still functional and can be subjected to detailed structural and functional analyses. Receptors from Alzheimer's brains will be compared with those from non-Alzheimer's brains, focusing on the receptors to GABA and Glutamate: the main inhibitory and excitatory neurotransmitters in the human brain. The effects of Amyloid beta will also be studied. All this will help determine the cause of Alzheimer's disease and help to develop new treatments.

Publications

Microtransplantation of ligand-gated receptor-channels from fresh or frozen nervous tissue into Xenopus oocytes: a potent tool for expanding functional information. Eusebi F, Palma E, Amici M, Miledi R.Prog Neurobiol. 2009 May;88(1):32-40.  

Design, synthesis, and biological evaluation of a scaffold for iGluR ligands based on the structure of (-)-kaitocephalin. Vaswani RG, Limon A, Reyes-Ruiz JM, Miledi R, Chamberlin AR. Bioorg Med Chem Lett. 2009 Jan 1;19(1):132-5.  

Microtransplantation of neurotransmitter receptors from postmortem autistic brains to Xenopus oocytes. Limon A, Reyes-Ruiz JM, Miledi R. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10973-7.  

Properties of GluR3 receptors tagged with GFP at the amino or carboxyl terminus. Limon A, Reyes-Ruiz JM, Eusebi F, Miledi R. Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15526-30.  

Properties of glutamate receptors of Alzheimer's disease brain transplanted to frog oocytes. Bernareggi A, Duenas Z, Reyes-Ruiz JM, Ruzzier F, Miledi R. Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2956-60.  

Altered GABA neurotransmission in Alzheimer's diseased brain. Limon A, Reyes-Ruiz JM, Miledi R. [PMID:nd][link not available]
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