Molecular and cellular aspects of age-related cognitive decline and Alzheimer's disease

Abstract

As the population of people aged 60 or older continues to rise, it has become increasingly important to understand the molecular basis underlying age-related cognitive decline. In fact, a better understanding of aging biology will help us identify ways to maintain high levels of cognitive functioning throughout the aging process. Many cellular and molecular aspects of brain aging are shared with other organ systems; however, certain age-related changes are unique to the nervous system due to its structural, cellular and molecular complexity. Importantly, the brain appears to show differential changes throughout the aging process, with certain regions (e.g. frontal and temporal regions) being more vulnerable than others (e.g. brain stem). Within the medial temporal lobe, the hippocampus is especially susceptible to age-related changes. The important role of the hippocampus in age-related cognitive decline and in vulnerability to disease processes such as Alzheimer's disease has prompted this review, which will focus on the complexity of changes that characterize aging, and on the molecular connections that exist between normal aging and Alzheimer's disease. Finally, it will discuss behavioral interventions and emerging insights for promoting healthy cognitive aging.

Keywords: Aging; Alzheimer’s disease; Cognition; Hippocampus; Molecular mechanisms.

Fig. 1

Aging and Hippocampal Signaling Pathways. Group 1 mGluR stimulation leads to subsequent activation of the downstream kinases including PKC, ERK, and mTOR. Subsequent activation of transcription factors such as CREB and ELK-1 within the nucleus induces trasncription of immediate early genes such as Homer1a, Arc, and Zif268. Homer1a is released into the cytosol and disrupts Homer1c/mGluR5 binding, whereas the IEGs Arc and Zif268 promote expression of genes essential for learning and memory to occur. Changes in in the expression ratio of Homer1a:Homer1c, cell surface expression of mGluR5, and activity of PKC, ERK, and mTOR are thought to play a role in successful cognitive aging.

Fig. 2

APP Processing and AD-Aging Pathways. (A) APP is a type 1 membrane protein consisting of a large extracellular domain, a single membrane-spanning domain, and a small cytoplasmic tail. APP cleavage occurs in a 2-step process. First, BACE-1 mediated cleavage at the β site generates a large N-terminal fragment that is secreted into the extracellular milieu and a small C-terminal fragment (C99) that remains membrane-bound. In the second step, C99 is cleaved at the γ site by γ-secretase to produce Aβ and AICD. Both Aβ and AICD have been shown to promote various aspects of Alzheimer’s disease pathology. (B) Possible impact of established aging pathways in the pathogenesis and/or progression of AD. Description is in the text.

Fig. 3

IGF-1R Signaling. Schematic view of the IGF-1R signaling pathway. Description is in the text.