Abstract
Cognitive decline is one of the many characteristics of aging. Reduced long-term potentiation (LTP) and long-term depression (LTD) are thought to be responsible for this decline, although the precise mechanisms underlying LTP and LTD dampening in the old remain unclear. We previously showed that aging is accompanied by the loss of cholesterol from the hippocampus, which leads to PI3K/Akt phosphorylation. Given that Akt de-phosphorylation is required for glutamate receptor internalization and LTD, we hypothesized that the decrease in cholesterol in neuronal membranes may contribute to the deficits in LTD typical of aging. Here, we show that cholesterol loss triggers p-Akt accumulation, which in turn perturbs the normal cellular and molecular responses induced by LTD, such as impaired AMPA receptor internalization and its reduced lateral diffusion. Electrophysiology recordings in brain slices of old mice and in anesthetized elderly rats demonstrate that the reduced hippocampal LTD associated with age can be rescued by cholesterol perfusion. Accordingly, cholesterol replenishment in aging animals improves hippocampal-dependent learning and memory in the water maze test.
Highlights
Aging is associated with cognitive decline, such that individuals older than 65 develop cognitive deficits or age-associated memory impairments
The magnitude of the long-term depression (LTD) response seems to depend on the efficacy of AMPAR internalization, which is in turn dependent on Akt dephosphorylation, glycogen synthase kinase 3 beta (GSK3b) activation, and receptor endocytosis
The normalization of Akt to b-actin showed that there was no change in total Akt following stimulation and that the amount of phosphorylated form of the serine–threonine kinase Akt (p-Akt)/b-actin only decreased in young mice after NMDA stimulation (Fig 1A)
Summary
Aging is associated with cognitive decline, such that individuals older than 65 develop cognitive deficits or age-associated memory impairments. The hippocampus, a brain structure that is central to the formation of declarative and other types of memory, is sensitive to aging. These impairments are not paralleled by an increase in neuronal death (Burke & Barnes, 2006), indicative that more subtle mechanisms must be affected by aging to produce memory decline. We previously showed that the phosphorylated form of the serine–threonine kinase Akt (p-Akt) accumulates in old hippocampal neurons, both in vivo and in vitro (Martin et al, 2008, 2011; Trovoet al, 2013), which probably reflects the strong need for survival signaling. P-Akt phosphorylation negatively regulates long-term depression (LTD), a key process in learning and memory (see below and Peineau et al, 2007)
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