Late-Onset Alzheimer's Disease, Heating up and Foxed by Several Proteins: Pathomolecular Effects of the Aging Process

Article type: Review Article

Authors: Perez, Felipe P.^a | Bose, David^a | Maloney, Bryan^b | Nho, Kwangsik^c | Shah, Kavita^d | Lahiri, Debomoy K.^{e; *}

Affiliations: [a] Department of Medicine, Geriatric Medicine Division, Indiana University School of Medicine, Indianapolis, IN, USA | [b] Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA | [c] Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA | [d] Department of Chemistry, Purdue University, West Lafayette, IN, USA | [e] Department of Psychiatry, and of Medical & Molecular Genetics, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA

Correspondence: [*] Correspondence to: Dr. D.K. Lahiri, Department of Psychiatry, Indiana University School of Medicine, 791 Union Drive, Indianapolis, IN 46202, USA. Tel.: +1 317 274 2706; Fax: +1 317 274 1365; E-mail: [email protected].

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.

Keywords: Amyloid, autophagy, cognition, dementia, heat-shock, neurodegeneration, protein aggregation, protein degradation, stress, transcription factor

DOI: 10.3233/JAD-131544

Journal: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 1-17, 2014