Lowered levels of nicotinic acetylcholine receptors and elevated apoptosis in the hippocampus of brains from patients with type 2 diabetes mellitus and db/db mice

Abstract

Cognitive impairment caused by diabetes has been gradually recognized. Generally, nicotinic acetylcholine receptors (nAChRs) play an important role in the pathogenesis in dementia disorders including Alzheimer's disease (AD). However, the expression of nAChRs in the brains of type 2 diabetes mellitus (T2DM) is unexplored. This study explored the alterations of nAChRs in the postmortem brains of patients with T2DM and brains of db/db mice. Morris water maze test was used to appraise the ability of spatial learning and memory; Western blotting and RT-qPCR were performed to determine the expressions of target protein and mRNA, respectively; TUNEL was used to detect the apoptosis of neurons. We found that the protein levels of nAChR α7 and α4 subunits were significantly decreased and the apoptosis rates in neurons elevated in the hippocampus of T2DM patients and db/db mice as comparison to controls. Furthermore, the db/db mice exhibited the impaired cognition, the elevated level of pro-apoptotic protein and the reduced level of anti-apoptotic and synaptic proteins. This study shows the lowered level of nAChR α7 and α4 subunits and the elevated apoptosis in the hippocampus of T2DM patients and db/db mice, which might help explain the impaired cognition in T2DM.

Impaired spatial navigation and age‐dependent hippocampal synaptic dysfunction are associated with chronic inflammatory response in db/db mice

“…We first demonstrated that adult db/db mice exhibit impaired spatial learning and recall in the MWM. Our findings are in line with previous reports which have demonstrated that db/db mice present impaired spatial memory in the MWM (Ramos-Rodriguez et al, 2013;Ren et al, 2021;Wang et al, 2021;Xu et al, 2020) (reviewed in Watanabe & Sakamoto, 2021). In our present study, we demonstrate that 3-to 5-month-old T2DM mice exhibit significant impairments in spatial acquisition in the MWM.…”

Neuroprotective effect of alpha‐pinene is mediated by suppression of the TNF‐α/NF‐κB pathway in Alzheimer's disease rat model

“…[35] There is a close relationship between the level of BDNF and α7 nAChR in the brain so that the level of both molecules in the brain of diabetic model mice decreases, and consequently, the apoptosis of neurons in the hippocampus increases. [36] In our study, the expression of α7 nAChR increased in the hippocampus of Aβ-P rats in the same way as BDNF. PNU-282987 and GTS-21 (both α7 nAChR agonists) stimulate PI3K/Akt and ERK/CREB signaling and increase BDNF expression.…”

Single-Cell Sequencing Analysis of the db/db Mouse Hippocampus Reveals Cell-Type-Specific Insights Into the Pathobiology of Diabetes-Associated Cognitive Dysfunction

“…Additionally, numerous clinical studies have shown that diabetes mellitus is closely related to vascular dementia, as well as Alzheimer’s disease (AD) ( 5 , 6 ). Multiple studies have demonstrated that factors such as neuronal apoptosis, oxidative stress, neuroinflammation and altered neurogenesis may play a role in DCD ( 7 , 8 ), in which oxidative stress and neuroinflammation are early-onset mechanism in diabetic encephalopathy ( 9 , 10 ). The hippocampus plays a vital role in learning and memory, and the impairment of its function is linked to DCD ( 11 ).…”