Warren J. Strittmatter, MD

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• Neurological Disorders

Division Chief

Department / Division:
Medicine / Neurology

Address:
DUMC 2900
Durham, NC 27710

Appointment Telephone:
919-668-7600

Office Telephone:
919-684-0053

Fax Telephone:
919-681-7198

• MD, Duke University School of Medicine, 1973

• Neurology, Duke University Medical Center, 1974-1977
• National Institutes of Health (Maryland), 1977-1979

Clinical Interests:
Alzheimer's disease, dementia, and other memory disorders

Research Interests:
Apolipoprotein (apoE) has been recently implicated in the pathogenesis of Alzheimer's disease (A.D.). One of the apoE alleles, e4, behaves as an autosomal co-dominant trait in the majority of late-onset and sporadic A.D.. The aopE4 gene dose is a major risk-factor susceptibility gene for A.D. with homozygosity for this allele virtually sufficient to cause disease by age 80, and with 50% of homozygous patients developing disease by age 68. Incontrast, the e2 and e3 alleles decrease the probability of disease, and increase the age of onset. Thus the inherited apoE allele determines in part, the risk of developing A.D., and determines the rate of disease progression. Interactions of apoE protein with other molecules is therefore critical in the disease process, with isoforms-specific interactions of apoE determining th eprobability, and rate, of disease expression.
The three common protein isoforms of apoE; E2, E3, E4, differ from each other by one amino acid, which determines their profoundly differing interactions with other proteins. In vitro, apoE4 binds BA peptide faster, and with a different pH dependence, than does apoE3. This isoform-specific difference observed in vitro correlates with the greater BA peptide amyloid burden deposited in situ in homozygous e4 A.D. patients, compared with homozygous e3 A.D. patients. Paired-helical filaments of the neurofibrillary tangle are composed of tau protein. ApoE3 avidly binds tau in vitro, forming a complex not disociated by boiling in SDS. In contrast, apoE4 does not form such a complex. Isoform-specific interactions of apoE with tau could alter tau function or metabolism.

Representative Publications:
4) Sana D, Weisgraber KH, Mahley RW, Huang DY, Russell SJ, Saunders A, Schmechel D, Wisniewski T, Frangione B, Roses AD and Strttmatter WJ: Apolipoprotein E associates with AB amyloid peptide to form novel monofibrils in vitro: Isoform apoE4 associates more efficiently than apoE3. J Clin Invest 94:860-869, 1994. (1994)

3) Corder EH, Saunders AM, Strittmatter WJ, Schmechel D, Gaskell P, Small GW, Roses AD, Haines JL, and Pericak-Vance MA: Apolipoprotein E gene dose affects the risk of Alzheimer disease. Science, 261:921-923, 1993. (1993)

2) Strittmatter WJ, Weisgraber KH, Huang D, Dong L-M, Salvesen GS, Pericak-Vance M, Schmechel D, Saunders AM, Goldgaber DM, and Roses AD: Binding of human apolipoprotein E to BA4 peptide: Isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci 90:8098-8102, 1993. (1993)

1) Strittmatter WJ, Saunders AM , Pericak-Vance M, Salvesen GS, Enghild J. and Roses AD: Apolipoprotein E: High avidity binding to BA amyloid and increased frequency of type 4 isoform in familiar Alzheimer Disease. Proc Natl Acad Sci 90:1977-1981, 1993. (1993)

Strittmatter WJ, Saunders Am, Goedert M, Weisgraber K, Dong L-M, Jakes R, Huang DY, Pericak-Vance M, Schmechel D, and Roses AD: Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: Implications for Alzheimer disease. Proc Natl Acad Sci, 91:1183-1186.