LiveWorld Transcripts

Bio Online presents

Jim Geddes, Ph.D., Mark Gurney, Ph.D., Ole Isacson, M.D., and Li-Huei Tsai, Ph.D.
Discussion about Alzheimer's

January 12, 1999

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Ole Isacson, M.D.: We have investigated how the processing of the amyloid precursor protein is regulated by cholinergic nerve cells in the brain. The cholinergic nerve terminals have been shown to be selectively reduced in Alzheimer brains and our finding that some of the cholinergic receptors, the specific M-1 type, can reduce levels of amyloid precursor protein suggests that this may be a way to reduce amyloid load in the brain.

Jeff Kuret, Ph.D.: We've discovered a new molecular link between the 3 hallmark pathologies of Alzheimer's disease. The protein is a protein kinase that is capable for phosphorylating tau protein present in the neurofibrillary pathology and perhaps something else in the GVDs. Because protein kinases are important regulatory molecules, there is an opportunity to have a causal relationship between the 3 pathologies of Alzheimer's disease.

Li-Huei Tsai, Ph.D.: My laboratory has identified a protein kinease, Cdk5, together with its regulatory activator, p35, that play a pivitol role in the development of the central nervous system. Recently, we found that a truncated form of p35, termed p25, is vastly elevated in Alzheimer's Disease brains. The resulting p25 and cdk5 kinase can hyperphosphorylate tau and cause profound cytoskeleton collapse in death in neurons. Therefore, the conversion of p35 to p25 is likely to play a role in the pathogenises of Alzheimer's disease.

AmySr: These recent discoveries provide new targets for drugs. Will inhibition of any one target be sufficient, or will it be necessary to target multiple sites?

Mark Gurney, Ph.D.: Most of us in the pharmaceutical industry feel that the treatment of AD will require multiple points of intervention, much like the treatment for cancer and HIV infection, which depend on multiple therapeutic agents. So perhaps an M-1 receptor blocker, beta secretase and a p35/cdk5 inhibitor will be the optimal treatament for Alzheimer's.

Ph9: Dr. Gurney, are Asp2 levels or activity increased in Alzheimer's disease?

Mark Gurney, Ph.D.: We don't know.

JohnSmt: Dr. Gurney, you mention in the paper that Asp2 is present in other organs, such as the pancreas, and may have a normal function in addition to contributing to the formation of beta-amyloid. Any clues as to what is the normal role of Asp2?

Mark Gurney, Ph.D.: We know that, in terms of Mrna expression, the pancreas is the tissue with the highest level of Asp2 or a beta secretase in transcription. We know that in the pancreas the transcripts are present in the acnair of the exocrine pancreas, so perhaps the enzyme plays a role in processing of pancreatic zydomen enzymes. But so far we do not know what its natural substrate is. We also expect that the enzyme has a normal function in the brain, other than the processing of A-beta peptites, but what that might be, we do not know as of yet.

FrogDogger: What is the function of amyloid precursor protein?

Ole Isacson, M.D.: The normal function of the amyloid precursor protein is not known. However, from its normal position in the cell membrane, it can be cleaved to be released into the extra cellular space where it can interact with other cells to have a trophic effect. Other components of the APP molecules, such as the A-beta, can also directly interact with neurotransmitter function. For example, A-beta has been shown to inhibit acetyeholine relief.

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