Brain aging as a cause of alzheimer’s disease

Toshiharu Suzuki, Ayano Kimura, Kyoko Chiba, Tadashi Nakaya, Saori Hata

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Alzheimer’s disease (AD) is the most common form of senile dementia. Identification of genes causally associated with familial Alzheimer’s disease (FAD) advanced our understanding of the molecular mechanisms of AD pathogenesis. However, FAD is much less common than sporadic Alzheimer’s disease (SAD), which constitutes the majority of cases. Despite its similar pathology (albeit at a later age of onset), SAD is not linked to mutations in FAD-associated genes. In both FAD and SAD, the generation and oligomerization of amyloid β (Aβ) peptide play central roles in neurotoxicity, but it remains unclear how qualitative and quantitative alterations in Aβ occur in SAD patients in the absence of causative mutations. The predominant risk factor for SAD is aging, suggesting that some as-yetunknown alterations in the aged brain augment the amyloidogenic metabolism of APP and promote the neural toxicity of Aβ oligomers. In this chapter, we discuss potential biochemical changes in amyloid β precursor protein (APP) and proteins related to APP metabolism and function in the aged brain. APP axonal transport, membrane microlocalization and metabolism, including generation of Aβ in neurons, are regulated by interactions with several cytoplasmic proteins and phosphorylation of the APP cytoplasmic region. Age-related decline or aberration in the regulation of APP transport, localization and metabolism may induce generation of altered Aβ. Here, we focus on APP phosphorylation at threonine 668 in the cytoplasmic domain and the roles of APP regulatory proteins, including X11-like (X11L), JIP1, kinesin-1, and Alcadein, on the regulation of APP metabolism and intracellular trafficking.

Original languageEnglish
Title of host publicationAging Mechanisms
Subtitle of host publicationLongevity, Metabolism, and Brain Aging
PublisherSpringer Japan
Pages305-318
Number of pages14
ISBN (Electronic)9784431557630
ISBN (Print)9784431557623
DOIs
Publication statusPublished - 2015 Jan 1
Externally publishedYes

Keywords

  • Alcadein
  • Alzheimer’s disease
  • Amyloid β peptide
  • APP
  • Brain aging
  • JIP1
  • Kinesin
  • p3-Alc
  • Protein phosphorylation
  • X11-like

ASJC Scopus subject areas

  • Medicine(all)
  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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