Abstract
Hippocampal neurogenesis plays an important role in learning and memory function throughout life. Declines in this process have been observed in both aging and Alzheimer’s disease (AD). Type 2 Diabetes mellitus (T2DM) is a disorder characterized by insulin resistance and impaired glucose metabolism. T2DM often results in cognitive decline in adults, and significantly increases the risk of AD development. The pathways underlying T2DM-induced cognitive deficits are not known. Some studies suggest that alterations in hippocampal neurogenesis may contribute to cognitive deterioration, however, the fate of neurogenesis in these studies is highly controversial. To address this problem, we utilized two models of T2DM: (1) obesity-independent MKR transgenic mice expressing a mutated form of the human insulin-like growth factor 1 receptor (IGF-1R) in skeletal muscle, and (2) Obesity-dependent db/db mice harboring a mutation in the leptin receptor. Our results show that both models of T2DM display compromised hippocampal neurogenesis. We show that the number of new neurons in the hippocampus of these mice is reduced. Clone formation capacity of neural progenitor cells isolated from the db/db mice is deficient. Expression of insulin receptor and epidermal growth factor receptor was reduced in hippocampal neurospheres isolated from db/db mice. Results from this study warrant further investigation into the mechanisms underlying decreased neurogenesis in T2DM and its link to the cognitive decline observed in this disorder.
Highlights
Hippocampal neurogenesis plays an important role in learning and memory function throughout life
This study addresses discrepancies in the literature concerning the fate of neurogenesis in Type 2 Diabetes mellitus (T2DM) mouse models
This may imply that dysfunction of hippocampal neurogenesis in T2DM may contribute to the development of Alzheimer’s disease (AD)
Summary
Hippocampal neurogenesis plays an important role in learning and memory function throughout life. The increased risk of AD in type 2 diabetes mellitus (T2DM) patients suggests that systemic processes in T2DM lead to brain pathology and cognitive impairments. Another study reports increased number of BrdU + or DCX + cells in the SVZ, SGZ and cortex of db/ db mice. Treatment of the neonatal mice with metformin following hypoxia-induced brain injury facilitated neurogenesis and led to functional recovery[22] This effect has been proposed to be mediated via insulin receptor substrate 121, while another study suggests that the effect on selfrenewal and proliferation occurs via the p53 family member and transcription factor TAp73, and it promotes neuronal differentiation of these cells by activating the 5′ adenosine monophosphate-activated protein kinase/ protein kinase C/transcriptional coactivator CREB-binding protein pathway AMPK-aPKC-CBP pathway[20,23]. These studies suggest that while there is a possible connection between hippocampal neurogenesis and cognitive deficits in T2DM, the fate of hippocampal neurogenesis in T2DM is yet to be established
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