Hippocampal calcium dysregulation at the nexus of diabetes and brain aging

Abstract

Accumulating evidence is associating disorders of lipid and glucose metabolism, including the overlapping conditions of insulin resistance/metabolic syndrome, obesity and diabetes, with moderate cognitive impairment in normal aging and elevated risk of Alzheimer’s disease. It appears that a common feature of these conditions is deficient insulin signaling, likely affecting the brain as well as canonical peripheral target tissues. A number of studies have documented that insulin directly affects brain processes and that reduced insulin signaling results in impaired learning and memory. Several studies have also shown that deficient insulin signaling induces Ca2+ dysregulation in neurons. Because brain aging is associated with substantial Ca2+ dyshomeostasis, it has been proposed that deficient insulin signaling exacerbates or accelerates aging-related Ca2+ dyshomeostasis. However, there have been few studies examining insulin interactions with Ca2+ regulation in aging animals. We have been testing predictions of the Ca2+ dysregulation/diabetes/brain aging hypothesis and have found that insulin and insulin sensitizers (thiazolidinediones) target several hippocampal Ca2+-related processes affected by aging, including larger Ca2+ transients and Ca2+-dependent afterhyperpolarizations, and counteract the effects of aging on those processes. Thus, while additional testing is needed, the results to date are consistent with the view that effects of deficient insulin signaling on brain aging are mediated in part by neuronal Ca2+ dyshomeostasis.

The BMP2 nuclear variant, nBMP2, is expressed in mouse hippocampus and impacts memory

“…The mildly impaired object recognition memory we observed is consistent with the calcium hypothesis of brain aging, which holds that “sustained disruption of mechanisms that normally regulate intracellular Ca 2+ signaling is pivotal for triggering adverse changes in the functioning of neurons”47. Sustained Ca 2+ dysregulation in neurons has also been implicated in the cognitive decline associated with obesity, diabetes, insulin resistance/metabolic syndrome, and Alzheimer disease484950. Additional studies are needed to fully characterize the mechanistic relationships that link nBMP2 with hippocampal LTP, but the evidence so far is consistent with our hypothesis that absence of nBMP2 from the nucleus leads to dysregulation of intracellular Ca 2+ signaling.…”

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…Impaired cerebral glucose utilization in the prefrontal cortex is inversely associated with body mass index in human subjects (Volkow et al, 2009), suggesting an adverse effect of a chronic positive energy balance on neuronal bioenergetics. Rats or mice maintained on high-fat and/or high-sugar diets, and diabetic animals, exhibit many of the cellular and molecular hallmarks of brain aging including oxidative damage (Elahi et al, 2016), neuroinflammation (Jayaraman et al, 2014), impaired neuronal Ca 2+ homeostasis (Thibault et al, 2013), impaired autophagy (Li et al, 2017), and dysregulation of neuronal network activity (Margineanu et al, 1998). Insulin-resistant mice exhibit impaired hippocampal neurogenesis, which is associated with oxidative stress, inflammation, and impaired hippocampus-dependent spatial learning and memory (Lindqvist et al, 2006; Stranahan et al, 2008a; Gurung et al, 2016).…”

Network models predict that pyramidal neuron hyperexcitability and synapse loss in the dlPFC lead to age-related spatial working memory impairment in rhesus monkeys

“…In vitro experiments have shown synaptic facilitation in PFC pyramidal neurons (Hempel et al, 2000;Wang et al 2006). Several other studies have shown age-related changes in synaptic plasticity (not modeled here), some correlating these changes with learning and memory deficits (Norris et al, 1998a(Norris et al, , 1998bBach et al, 1999;Rosenzweig and Barnes, 2003;Thibault et al, 2007;Gant et al, 2011;Thibault et al, 2013;Gant et al, 2014;Gant et al, 2015).…”