Dr. Levine's Lab: Summary

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LeVine Lab

BACKGROUND

Alzheimer’s Disease May Share Etiology with Other Chronic Neurodegenerative Diseases -Chronic neurodegenerative diseases affect a variety of specific areas of the brain giving rise to a spectrum of symptoms ranging from dementia involving different cognitive modalities, to loss of motor control and coordination, and visual deficits. Brain malfunction is due to loss of synaptic connections and the death of neuronal cells. Despite different symptoms which depend on the brain area from which the cells are lost, these chronic neurodegenerative diseases share the characteristic accumulation of a misfolded protein, different for each disease, which frequently deposits in or around neuronal cells.

These different proteins assemble into soluble oligomers and insoluble β-sheet-rich amyloid fibril structures which are similarly toxic to cells even though their amino acid sequences differ. Since after birth brain neurons are postmitotic, they are not replaced and are particularly vulnerable to low level long-term insults. The many similar properties of these toxic protein complexes have led us to group these chronic neurodegenerative diseases as cerebral proteopathies.

1) Walker, L. C. & LeVine, H., III. (2002) Proteopathy: the next therapeutic frontier? Curr Opin Investig Drugs 3: 782-787.

2) Walker, L. C., Bian, F., Callahan, M. J., Lipinski, W. J., Durham, R. A. & LeVine, H. (2002) Modeling Alzheimer's disease and other proteopathies in vivo: Is seeding the key? Amino Acids 23: 87-93.

3) Walker, L. C. & LeVine, H. (2000) The cerebral proteopathies: neurodegenerative disorders of protein conformation and assembly. Mol Neurobiol 21: 83-95.

Alzheimer’s disease is believed to silently develop over a period of nearly forty years before becoming apparent. The subsequent deterioration to a vegetative mental state typically occurs over eight years but can last up to twenty years. Currently approved drugs for AD and Parkinson’s disease treat only the symptoms caused by cell loss. They do not address the root causes of the degeneration and thus do not significantly modify the progress of the disease.

b-Amyloid Peptide – Genetic forms of AD and the prominence of deposits of a 40-42 amino acid peptide in AD brains support the Amyloid Hypothesis as the causative agent in AD. The initial stage is believed to be the accumulation of polymerized forms of the b-amyloid peptide (Ab) in soluble multimeric and/or insoluble senile plaque deposits in the brain. Neuronal signaling mechanisms are disrupted causing hyperphosphorylation of tau, which normally stabilizes the microtubule structure trafficking materials the length of neurons which are the body’s largest cells. Hyperphosphorylated tau aggregates in the cell body, derailing the intracellular transport system eventually maturing into neurofibrillary tangles, the other misfolded protein pathology of AD.

1) Selkoe, D. J. and Schenk, D. (2003) ALZHEIMER'S DISEASE: Molecular Understanding Predicts Amyloid-Based Therapeutics. Annu Rev Pharmacol Toxicol 43: 545-584.

2) Walsh, D. M. and Selkoe, D. J. (2004) Oligomers on the brain: the emerging role of soluble protein aggregates in neurodegeneration. Protein Pept Lett 11: 213-228.

3) Helmuth, L. (2003) Detangling Alzheimer's disease. New insights into the biological bases of the most common cause of dementia are pointing to better diagnostics and possible therapeutics. Sci Aging Knowledge Environ 2003: oa2.

In the over 90% of AD cases which are non-genetic, accumulation of Ab is related to altered clearance or breakdown of the peptide from neuronal cells and the brain rather than increased synthesis. Deposits are not found outside of the brain. The brain buildup begins around age 50. Levels of soluble multimeric forms of Ab increase in human brain and in the brains of transgenic mice that produce the human sequence Ab. Histologically invisible soluble material gathers and Ab deposits in characteristic plaques in the brain parenchyma and around cerebral blood vessels.

A number of current therapeutic disease modifying strategies strive to reduce the amount of Ab present. These range from modulating the proteases that cleave Ab from its precursor protein, AbPP, immunologically depleting the Ab, or blocking the polymerization into multimeric and plaque forms of Ab.