Alzheimer's disease-like pathological features in transgenic mice expressing the APP intracellular domain

Kaushik Ghosal, Daniel L. Vogt, Man Liang, Yong Shen, Bruce Lamb, Sanjay W. Pimplikar

Research output: Contribution to journalArticle

177 Citations (Scopus)

Abstract

The hypothesis that amyloid-β (Aβ) peptides are the primary cause of Alzheimer's disease (AD) remains the best supported theory of AD pathogenesis. Yet, many observations are inconsistent with the hypothesis. Aβ peptides are generated when amyloid precursor protein (APP) is cleaved by presenilins, a process that also produces APP intracellular domain (AICD). We previously generated AICD-overexpressing transgenic mice that showed abnormal activation of GSK-3β, a pathological feature of AD. We now report that these mice exhibit additional AD-like characteristics, including hyperphosphorylation and aggregation of tau, neurodegeneration and working memory deficits that are prevented by treatment with lithium, a GSK-3β inhibitor. Consistent with its potential role in AD pathogenesis, we find AICD levels to be elevated in brains from AD patients. The in vivo findings that AICD can contribute to AD pathology independently of Aβ have important therapeutic implications and may explain some observations that are discordant with the amyloid hypothesis.

Original languageEnglish (US)
Pages (from-to)18367-18372
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number43
DOIs
StatePublished - 2009
Externally publishedYes

Fingerprint

Amyloid
Transgenic Mice
Alzheimer Disease
Glycogen Synthase Kinase 3
Presenilins
Peptides
Amyloid beta-Protein Precursor
Memory Disorders
Brain Diseases
Protein Domains
Short-Term Memory
Lithium
Pathology
Therapeutics

Keywords

  • Amyloid precursor protein
  • Neurodegeneration
  • Tau hyperphosphorylation

ASJC Scopus subject areas

  • General

Cite this

Alzheimer's disease-like pathological features in transgenic mice expressing the APP intracellular domain. / Ghosal, Kaushik; Vogt, Daniel L.; Liang, Man; Shen, Yong; Lamb, Bruce; Pimplikar, Sanjay W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 43, 2009, p. 18367-18372.

Research output: Contribution to journalArticle

Ghosal, Kaushik ; Vogt, Daniel L. ; Liang, Man ; Shen, Yong ; Lamb, Bruce ; Pimplikar, Sanjay W. / Alzheimer's disease-like pathological features in transgenic mice expressing the APP intracellular domain. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 43. pp. 18367-18372.
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