Late-onset Alzheimer's disease, heating up and foxed by several proteins: Pathomolecular effects of the aging process

Felipe P. Perez, David Bose, Bryan Maloney, Kwangsik Nho, Kavita Shah, Debomoy K. Lahiri

Research output: Contribution to journalReview article

10 Scopus citations

Abstract

Late-onset Alzheimer's disease (LOAD) is the most common neurodegenerative disorder in older adults, affecting over 50% of those over age 85. Aging is the most important risk factor for the development of LOAD. Aging is associated with the decrease in the ability of cells to cope with cellular stress, especially protein aggregation. Here we describe how the process of aging affects pathways that control the processing and degradation of abnormal proteins including amyloid-β (Aβ). Genetic association studies in LOAD have successfully identified a large number of genetic variants involved in the development of the disease. However, there is a gap in understanding the interconnections between these pathomolecular events that prevent us from discovering therapeutic targets. We propose novel, pertinent links to elucidate how the biology of aging affects the sequence of events in the development of LOAD. Furthermore we analyze and synthesize the molecular-pathologic-clinical correlations of the aging process, involving the HSF1 and FOXO family pathways, Aβ metabolic pathway, and the different clinical stages of LOAD. Our new model postulates that the aging process would precede Aβ accumulation, and attenuation of HSF1 is an 'upstream' event in the cascade that results in excess Aβ and synaptic dysfunction, which may lead to cognitive impairment and/or trigger 'downstream' neurodegeneration and synaptic loss. Specific host factors, such as the activity of FOXO family pathways, would mediate the response to Aβ toxicity and the pace of progression toward the clinical manifestations of AD.

Original languageEnglish (US)
Pages (from-to)1-17
Number of pages17
JournalJournal of Alzheimer's Disease
Volume40
Issue number1
DOIs
StatePublished - 2014

Keywords

  • Amyloid
  • autophagy
  • cognition
  • dementia
  • heat-shock
  • neurodegeneration
  • protein aggregation
  • protein degradation
  • stress
  • transcription factor

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology

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