Isoform-Specific Metabolism of Apolipoprotein E: Implications for Alzheimer ’s Disease
Inheritance of specific apolipoprotein E alleles determines, in large part, the risk and mean age of onset of late-onset familial and sporadic Alzheimer disease (AD) (see Strittmatter and Roses, 1995). The mechanism by which the apolipoprotein E isoforms differentially contribute to disease expression is, however, unknown. Many isoform-specific interactions of apolipoprotein E have been identified. Identification of isoform-specific interactions of apolipoprotein E give rise to testable hypotheses for the mechanism of pathogenesis of AD. An unresolved issue of increasing importance is the relationship between the structural pathological lesions and the cellular pathogenesis responsible for the clinical disease phenotype, progressive dementia.
KeywordsAlzheimer Disease Neurofibrillary Tangle Paired Helical Filament Sporadic Alzheimer Disease Clinical Disease Phenotype
Unable to display preview. Download preview PDF.
- Fleming L, Weisgraber KH, Strittmatter WJ, Troncoso JC, and Johnson GVW (1996): Differential binding of apoE isoforms to tau and other cytoskeletal proteins. Experimental Neurology (In Press).Google Scholar
- Huang DY, Goedert M, Jakes R, Weisgraber KH, Garner C, Saunders AM, Pericak-Vance M., Schmechel D, Roses AD, Strittmatter WJ (1994): Isoform-specific interactions of apolipoprotein E with the microtubule-associated protein MAP 2c: Implications for Alzheimer’s disease, Neuroscience Letters 182: 55–58.PubMedCrossRefGoogle Scholar
- Montine TJ, Huang DY, Valentine WM, Amarnath V, Saunders AM, Weisgraber KH, Graham DG, and Strittmatter WJ (1996a):, Crosslinking of apolipoprotein E by products of lipid peroxidation. J Neuropath Expt Neurology (In Press).Google Scholar
- Montine TJ, Amarnath V, Martin ME, Strittmatter WJ, and Graham DG (1996b), E-4-hydroxy-2-nonenal, is cytotoxic and covalently crosslinks cytoskeletal proteins in P19 neuroglial cells. Amer J Path (In Press).Google Scholar
- Sanan D, Weisgraber KH, Mahley RW, Huang DY, Russell SJ, Saunders A, Schmechel D, Wisniewski T, Frangione B, Roses AD and Strittmatter WJ (1994): 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.PubMedCrossRefGoogle Scholar
- Strittmatter WJ, Weisgraber KH, Huang D, Dong LM, Salvesen GS, Pericak-Vance M, Schmechel D, Saunders AM, Goldgaber DM, and Roses AD (1993b): Binding of human apolipoprotein E to βA4 peptide: Isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci 90: 8098–8102.PubMedCrossRefGoogle Scholar
- Strittmatter WJ, Weisgraber KH, Goedert M, Saunders AM, Huang D, Corder, EH, Dong LM, Jakes R, Alberts MJ, Gilbert JR, Schmechel DE, Pericak-Vance MA, and Roses AD, (1994a) Hypothesis: Microtubule instability and paired helical filament formation in the Alzheimer disease brain as a function of apolipoprotein E genotype. Exptl Neurol 125:163–171.CrossRefGoogle Scholar
- Strittmatter WJ, Saunders AM, Goedert M, Weisgraber K, Dong LM, Jakes R, Huang DY, Pericak-Vance M, Schmechel D, and Roses AD (1994b) Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: Implications for Alzheimer disease. Proc Natl Acad Sci 91:11183–11186.PubMedCrossRefGoogle Scholar
- Weisgraber KH (1994): Apolipoprotein E: Structure-Function Relationships, in Advances in Protein Chemistry, Vol 45, pp.249–301.Google Scholar