The ageing cortical synapse: hallmarks and implications for cognitive decline

Abstract

Individual differences are a hallmark of cognitive and synaptic ageing. Neurobiological differences between individuals of the same chronological age may underlie the preservation of cognitive abilities in advanced age versus cognitive impairment. In general, age-related cognitive impairments that occur in the absence of neurodegenerative diseases are not associated with loss of cortical neurons. Instead, they seem to be associated with subtle synaptic alterations. The prefrontal cortex controls higher-order, complex behaviours. A hallmark of cognitive ageing is impaired prefrontal function, including impairments in spatial working memory. One synaptic correlate of age-related impairments in working memory that has been identified in monkeys is a loss of thin spines in layer 3 of the dorsolateral prefrontal cortex. The medial temporal lobe, including the hippocampus, is responsible for memories of everyday events. Mild impairments in medial temporal lobe function are also observed in cognitive ageing. A range of synaptic alterations in hippocampal function that correlate with age-related memory impairments have been described. These have been observed in all subfields of the hippocampus and differ between subfields. A notable synaptic alteration in the aged monkey hippocampus is the loss of multisynaptic boutons in the dentate gyrus, which correlates with cognitive impairments. Cyclical oestradiol treatment of aged, surgically menopausal monkeys increases the density of thin dendritic spines in the prefrontal cortex and improves working memory. This illustrates the potential of synaptic and cognitive changes in ageing to be reversible. Loss of synapses may predispose neurons to degeneration in disease states. Thus, a better understanding of mechanisms that promote stability of synapses in ageing should lead not only to amelioration of age-related cognitive impairments but may also affect vulnerability to neurodegenerative diseases.