Central role for NMDA receptors in redox mediated impairment of synaptic function during aging and Alzheimer’s disease

• Published in: Behavioural brain research 2017-03, Vol.322 (Pt B), p.223-232
• Main Authors: Foster, T.C, Kyritsopoulos, C., Kumar, A.
• Format: Article
• Language: English
• Subjects: Aging; Aging - metabolism; Alzheimer Disease - metabolism; Alzheimer's disease; Animals; Calcium dysregulation; Cognitive function; Hippocampus; Humans; Intracellular calcium stores; NMDA receptor; Oxidation-Reduction; Receptors, N-Methyl-D-Aspartate - metabolism; Synapses - metabolism; Synaptic plasticity; Synaptic Transmission - physiology
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2016.05.012

•Brain regions that are vulnerable to Alzheimer’s disease are also vulnerable to aging; although, the mechanisms for selective vulnerability are unclear.•Altered synaptic plasticity associated with aging and the early stages of Alzheimer’s disease is thought to contribute to impaired memory.•For some vulnerable synapses, impaired synaptic plasticity during aging is due to Ca2+ dysregulation including N-methyl-d-aspartate receptor hypofunction in association with a rise in oxidative stress.•Molecules linked to Alzheimer’s disease, β-amyloid (Aβ) and mutated presenilin-1, induce changes which mimic senescent physiology, suggesting potential points of interaction between aging and Alzheimer’s disease and possible reasons for the observation that aging is a major risk factor for Alzheimer’s disease. Increased human longevity has magnified the negative impact that aging can have on cognitive integrity of older individuals experiencing some decline in cognitive function. Approximately 30% of the elderly will have cognitive problems that influence their independence. Impaired executive function and memory performance are observed in normal aging and yet can be an early sign of a progressive cognitive impairment of Alzheimer’s disease (AD), the most common form of dementia. Brain regions that are vulnerable to aging exhibit the earliest pathology of AD. Senescent synaptic function is observed as a shift in Ca2+-dependent synaptic plasticity and similar mechanisms are thought to contribute to the early cognitive deficits associated with AD. In the case of aging, intracellular redox state mediates a shift in Ca2+ regulation including N-methyl-d-aspartate (NMDA) receptor hypofunction and increased Ca2+ release from intracellular stores to alter synaptic plasticity. AD can interact with these aging processes such that molecules linked to AD, β-amyloid (Aβ) and mutated presenilin 1 (PS1), can also degrade NMDA receptor function, promote Ca2+ release from intracellular stores, and may increase oxidative stress. Thus, age is one of the most important predictors of AD and brain aging likely contributes to the onset of AD. The focus of this review article is to provide an update on mechanisms that contribute to the senescent synapse and possible interactions with AD-related molecules, with special emphasis on regulation of NMDA receptors.