Publication Detail

The publication detail shows the title, authors (with indicators showing other profiled authors), information on the publishing organization, abstract and a link to the article in PubMed. This abstract is what is used to create the fingerprint of the publication. If any grants are referenced by the publication, they will be listed here as well.

Hypothesis: microtubule instability and paired helical filament formation in the Alzheimer disease brain are related to apolipoprotein E genotype.

W J Strittmatter; K H Weisgraber; M Goedert; A M Saunders; D Huang; E H Corder; L M Dong; R Jakes; M J Alberts; J R Gilbert (Profiled Authors: Strittmatter, Warren J; Saunders, Ann M; Goedert, Michel; Gilbert, John R)

Department of Medicine (Neurology), Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, North Carolina 27710.
Experimental neurology 1994;125(2):163-71; discussion 172-4.

A genetic classification of Alzheimer disease(s) (AD) is presented. We describe a potential metabolic process in individuals who inherit apolipoprotein E-epsilon 4 (APOE4, gene; apoE4, protein) alleles, leading to increased risk and earlier age of onset of late-onset Alzheimer disease. Apolipoprotein E-epsilon 3 (apoE3) binds to tau protein, possibly slowing the initial rate of tau phosphorylation and self-assembly into paired helical filaments (PHFs); apoE4 does not bind tau. Tau promotes microtubule assembly and stabilizes microtubules; hyperphosphorylated tau does not bind, thereby destabilizing microtubules. Hyperphosphorylated tau may self-assemble into PHFs. Over time a bias toward destabilization of microtubules and the formation of neurofibrillary tangles may occur in individuals who inherit APOE4 alleles, leading to a shorter functional neuronal life span. This hypothesis focuses attention on two important aspects of AD research design: (1) Although the inheritance of APOE4 is associated with increased risk and decreased age of onset, apoE4 does not directly cause the disease. Our data point to the absence of an important function of apoE3 or apoE2 in individuals who do not inherit these alleles as the genetically relevant metabolic factor. This has important implications for design of experiments directed toward understanding the relevant neuronal metabolism. (2) Should this hypothesis be proven and confirmed, targets for pharmaceutical therapy designed to mimic the metabolic function of apoE3 or apoE2 become a realistic preventive strategy.

3 Originating Grant

• 1.

  Schmechel, Donald E

  ALZHEIMER'S DISEASE RESEARCH CENTER

  1 May 2000 - 30 April 2005

  NATIONAL INSTITUTE ON AGING

  Total Funding: $ 16,537,307

• 2.

  ROSES, ALLEN D

  GENETICS OF LATE AND EARLY ONSET ALZHEIMERS DISEASE

  1 August 1988 - 31 July 1996

  NATIONAL INSTITUTE ON AGING

  Total Funding: $ 5,327,551

• 3.

  ROSES, ALLEN D

  ALZHEIMERS DISEASE RESEARCH CENTER

  30 September 1985 - 30 April 2000

  NATIONAL INSTITUTE ON AGING

  Total Funding: $ 17,660,528

Scientific Context

This section shows information related to the publication - computed using the fingerprint of the publication - including related publications, related experts and related grants with fingerprints representing significant amounts of overlap between their fingerprint and this publication. The red dots indicate whether those experts or terms appear within the publication, thereby showing potential and actual connections.