Hypothesis: Microtubule Instability and Paired Helical Filament Formation in the Alzheimer Disease Brain Are Related to Apolipoprotein E Genotype

Warren J. Strittmatter, Karl H. Weisgraber, Michel Goedert, Ann M. Saunders, David Huang, Elizabeth H. Corder, Li Ming Dong, Ross Jakes, Mark J. Alberts, John R. Gilbert, Seol Heui Han, Christine Hulette, Gillian Einstein, Donald E. Schmechel, Margaret A. Pericak-Vance, Allen D. Roses

Research output: Contribution to journalArticle

401 Citations (Scopus)

Abstract

A genetic classification of Alzheimer disease(s) (AD) is presented. We describe a potential metabolic process in individuals who inherit apolipoprotein E-ε{lunate}4 (APOE4, gene; apoE4, protein) alleles, leading to increased risk and earlier age of onset of late-onset Alzheimer disease. Apolipoprotein E-ε{lunate}3 (apoE3) binds to tau protein, possibly slowing the initial rate of tau phosphorylation and self-assembly into paired helical filments (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.

Original languageEnglish (US)
Pages (from-to)163-171
Number of pages9
JournalExperimental Neurology
Volume125
Issue number2
DOIs
StatePublished - Feb 1994

Fingerprint

Apolipoprotein E3
Apolipoprotein E4
Apolipoproteins E
Microtubules
Alzheimer Disease
Genotype
Apolipoprotein E2
Alleles
Brain
Age of Onset
tau Proteins
Neurofibrillary Tangles
Research Design
Phosphorylation
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • Neurology
  • Neuroscience(all)

Cite this

Strittmatter, W. J., Weisgraber, K. H., Goedert, M., Saunders, A. M., Huang, D., Corder, E. H., ... Roses, A. D. (1994). Hypothesis: Microtubule Instability and Paired Helical Filament Formation in the Alzheimer Disease Brain Are Related to Apolipoprotein E Genotype. Experimental Neurology, 125(2), 163-171. https://doi.org/10.1006/exnr.1994.1019

Hypothesis : Microtubule Instability and Paired Helical Filament Formation in the Alzheimer Disease Brain Are Related to Apolipoprotein E Genotype. / Strittmatter, Warren J.; Weisgraber, Karl H.; Goedert, Michel; Saunders, Ann M.; Huang, David; Corder, Elizabeth H.; Dong, Li Ming; Jakes, Ross; Alberts, Mark J.; Gilbert, John R.; Han, Seol Heui; Hulette, Christine; Einstein, Gillian; Schmechel, Donald E.; Pericak-Vance, Margaret A.; Roses, Allen D.

In: Experimental Neurology, Vol. 125, No. 2, 02.1994, p. 163-171.

Research output: Contribution to journalArticle

Strittmatter, WJ, Weisgraber, KH, Goedert, M, Saunders, AM, Huang, D, Corder, EH, Dong, LM, Jakes, R, Alberts, MJ, Gilbert, JR, Han, SH, Hulette, C, Einstein, G, Schmechel, DE, Pericak-Vance, MA & Roses, AD 1994, 'Hypothesis: Microtubule Instability and Paired Helical Filament Formation in the Alzheimer Disease Brain Are Related to Apolipoprotein E Genotype', Experimental Neurology, vol. 125, no. 2, pp. 163-171. https://doi.org/10.1006/exnr.1994.1019
Strittmatter, Warren J. ; Weisgraber, Karl H. ; Goedert, Michel ; Saunders, Ann M. ; Huang, David ; Corder, Elizabeth H. ; Dong, Li Ming ; Jakes, Ross ; Alberts, Mark J. ; Gilbert, John R. ; Han, Seol Heui ; Hulette, Christine ; Einstein, Gillian ; Schmechel, Donald E. ; Pericak-Vance, Margaret A. ; Roses, Allen D. / Hypothesis : Microtubule Instability and Paired Helical Filament Formation in the Alzheimer Disease Brain Are Related to Apolipoprotein E Genotype. In: Experimental Neurology. 1994 ; Vol. 125, No. 2. pp. 163-171.
@article{9b6d1aa8c3a94a388e68a6a15aa9a0c8,
title = "Hypothesis: Microtubule Instability and Paired Helical Filament Formation in the Alzheimer Disease Brain Are Related to Apolipoprotein E Genotype",
abstract = "A genetic classification of Alzheimer disease(s) (AD) is presented. We describe a potential metabolic process in individuals who inherit apolipoprotein E-ε{lunate}4 (APOE4, gene; apoE4, protein) alleles, leading to increased risk and earlier age of onset of late-onset Alzheimer disease. Apolipoprotein E-ε{lunate}3 (apoE3) binds to tau protein, possibly slowing the initial rate of tau phosphorylation and self-assembly into paired helical filments (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.",
author = "Strittmatter, {Warren J.} and Weisgraber, {Karl H.} and Michel Goedert and Saunders, {Ann M.} and David Huang and Corder, {Elizabeth H.} and Dong, {Li Ming} and Ross Jakes and Alberts, {Mark J.} and Gilbert, {John R.} and Han, {Seol Heui} and Christine Hulette and Gillian Einstein and Schmechel, {Donald E.} and Pericak-Vance, {Margaret A.} and Roses, {Allen D.}",
year = "1994",
month = "2",
doi = "10.1006/exnr.1994.1019",
language = "English (US)",
volume = "125",
pages = "163--171",
journal = "Experimental Neurology",
issn = "0014-4886",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - Hypothesis

T2 - Microtubule Instability and Paired Helical Filament Formation in the Alzheimer Disease Brain Are Related to Apolipoprotein E Genotype

AU - Strittmatter, Warren J.

AU - Weisgraber, Karl H.

AU - Goedert, Michel

AU - Saunders, Ann M.

AU - Huang, David

AU - Corder, Elizabeth H.

AU - Dong, Li Ming

AU - Jakes, Ross

AU - Alberts, Mark J.

AU - Gilbert, John R.

AU - Han, Seol Heui

AU - Hulette, Christine

AU - Einstein, Gillian

AU - Schmechel, Donald E.

AU - Pericak-Vance, Margaret A.

AU - Roses, Allen D.

PY - 1994/2

Y1 - 1994/2

N2 - A genetic classification of Alzheimer disease(s) (AD) is presented. We describe a potential metabolic process in individuals who inherit apolipoprotein E-ε{lunate}4 (APOE4, gene; apoE4, protein) alleles, leading to increased risk and earlier age of onset of late-onset Alzheimer disease. Apolipoprotein E-ε{lunate}3 (apoE3) binds to tau protein, possibly slowing the initial rate of tau phosphorylation and self-assembly into paired helical filments (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.

AB - A genetic classification of Alzheimer disease(s) (AD) is presented. We describe a potential metabolic process in individuals who inherit apolipoprotein E-ε{lunate}4 (APOE4, gene; apoE4, protein) alleles, leading to increased risk and earlier age of onset of late-onset Alzheimer disease. Apolipoprotein E-ε{lunate}3 (apoE3) binds to tau protein, possibly slowing the initial rate of tau phosphorylation and self-assembly into paired helical filments (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.

UR - http://www.scopus.com/inward/record.url?scp=0028269666&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028269666&partnerID=8YFLogxK

U2 - 10.1006/exnr.1994.1019

DO - 10.1006/exnr.1994.1019

M3 - Article

C2 - 8313935

AN - SCOPUS:0028269666

VL - 125

SP - 163

EP - 171

JO - Experimental Neurology

JF - Experimental Neurology

SN - 0014-4886

IS - 2

ER -