Objective.Numerous epidemiological studies have linked diabetes mellitus (DM) with an increased risk of developing Alzheimer’s disease (AD). However, whether or not diabetic encephalopathy shows AD-like pathology remains unclear.Research Design and Methods.Forebrain and hippocampal volumes were measured using stereology in serial coronal sections of the brain in streptozotocin- (STZ-) induced rats. Neurodegeneration in the frontal cortex, hypothalamus, and hippocampus was evaluated using Fluoro-Jade C (FJC). Aβaggregation in the frontal cortex and hippocampus was tested using immunohistochemistry and ELISA. Dendritic spine density in the frontal cortex and hippocampus was measured using Golgi staining, and western blot was conducted to detect the levels of synaptophysin. Cognitive ability was evaluated through the Morris water maze and inhibitory avoidant box.Results.Rats are characterized by insulin deficiency accompanied with polydipsia, polyphagia, polyuria, and weight loss after STZ injection. The number of FJC-positive cells significantly increased in discrete brain regions of the diabetic rats compared with the age-matched control rats. Hippocampal atrophy, Aβaggregation, and synapse loss were observed in the diabetic rats compared with the control rats. The learning and memory of the diabetic rats decreased compared with those of the age-matched control rats.Conclusions.Our results suggested that aberrant metabolism induced brain aging as characterized by AD-like pathologies.

Following a social defeat, the balanced establishment and extinction of aversive information is a beneficial strategy for individual survival. Abnormal establishment or extinction is implicated in the development of mental disorders. This study investigated the time course of the establishment and extinction of aversive information from acute social defeat and the temporal responsiveness of the basolateral amygdala (BLA), ventral hippocampus (vHIP) and medial prefrontal cortex (mPFC) in this process. Mouse models of acute social defeat were established by using the resident–intruder paradigm. To evaluate the engram of social defeat, the intruder mice were placed into the novel context at designated time to test the social behavior. Furthermore, responses of BLA, vHIP and mPFC were investigated by analyzing the expression of immediate early genes, such as zif268, arc, and c-fos. The results showed after an aggressive attack, aversive memory was maintained for approximately 7 days before gradually diminishing. The establishment and maintenance of aversive stimulation were consistently accompanied by BLA activity. By contrast, vHIP and mPFC response was inhibited from this process. Additionally, injecting muscimol (Mus), a GABA receptor agonist, into the BLA alleviated the freezing behavior and social fear and avoidance. Simultaneously, Mus treatment decreased the zif268 and arc expression in BLA, but it increased their expression in vHIP. Our data support and extend earlier findings that implicate BLA, vHIP and mPFC in social defeat. The time courses of the establishment and extinction of social defeat are particularly consistent with the contrasting BLA and vHIP responses involved in this process.

Rotenone is a mitochondrial complex I inhibitor, which can cause the death of dopaminergic (DA) neurons and Parkinson’s disease (PD). Currently, whether metformin has a protective effect on neurotoxicity induced by rotenone is unclear. The purpose of this study was to evaluate the potential protective effect of metformin against rotenone-induced neurotoxicity. PD animal model was established by unilateral rotenone injection into the right substantia nigra (SN) of C57BL/6 mice. The behavioral tests were performed by rotarod test and cylinder test. The numbers of TH-positive neurons and Iba-1 positive microglia in the SN were investigated by immunohistochemical staining. The mRNA levels of proinflammatory cytokines (TNF-α and IL-1β) and molecules involved in endoplasmic reticulum (ER) stress (ATF4, ATF6, XBP1, Grp78 and CHOP) in the midbrain were detected by Quantitative real-time PCR. This study showed that 50 mg/kg metform given orally daily, beginning three days before rotenone injection and conitnuing for 4 weeks following rotenone injection, significantly ameliorated dyskinesia, increased the number of TH-positive neurons and mitigated the activation of microglia in the SN in rotenone-induced PD mice. Furthermore, 50mg/kg metformin markedly down-regulated the expression of proinflammatory cytokines (TNF-α and IL-1β) and ER stress related genes (ATF4, ATF6, XBP1, Grp78 and CHOP) in rotenone-induced PD mice. Metformin has a protective effect on DA neurons against rotenone-induced neurotoxicity through inhibiting neuroinflammation and ER stress in PD mouse model.

The accumulation of human islet amyloid polypeptide (hIAPP) in pancreatic islets under induction by a high-fat diet plays a critical role in the development of type-2 diabetes mellitus (T2DM). T2DM is a risk factor of late-onset Alzheimer’s disease (AD). Nevertheless, whether hIAPP in combination with hyperlipidemia may lead to AD-like pathological changes in the brain remains unclear. hIAPP transgenic mice were fed with a high-fat diet for 6 or 12 months to establish the T2DM model. The accumulation of amylin, the numbers of Fluoro-Jade C (FJC)-positive and β-gal positive cells, and the deposition level of Aβ42 in the hippocampi of the transgenic mice were detected by using brain sections. Cytoplasmic and membrane proteins were extracted from the hippocampi of the transgenic mice, and the ratio of membrane GLUT4 expression to cytoplasmic GLUT4 expression was measured through Western blot analysis. Changes in the cognitive functions of hIAPP transgenic mice after 12 months of feeding with a high-fat diet were evaluated. hIAPP transgenic mice fed with a high-fat diet for 6 or 12 months showed elevated blood glucose levels and insulin resistance; increased amylin accumulation, number of FJC-positive and β-gal positive cells, and Aβ42 deposition in the hippocampi; and reduced membrane GLUT4 expression levels. hIAPP transgenic mice fed with a high-fat diet for 12 months showed reductions in social cognitive ability and passive learning ability. A high-fat diet increased amylin accumulation in the hippocampi of hIAPP transgenic mice, which presented AD-like pathology and behavior characterized by neural degeneration, brain aging, Aβ42 deposition, and impaired glucose utilization and cognition.