Empagliflozin reduces vascular damage and cognitive impairment in a mixed murine model of Alzheimer’s disease and type 2 diabetes

Abstract

Background: Both Alzheimer's disease (AD) and type 2 diabetes (T2D) share common pathological features including inflammation, insulin signaling alterations, or vascular damage. AD has no successful treatment, and the close relationship between both diseases supports the study of antidiabetic drugs to limit or slow down brain pathology in AD. Empagliflozin (EMP) is a sodium-glucose co-transporter 2 inhibitor, the newest class of antidiabetic agents. EMP controls hyperglycemia and reduces cardiovascular comorbidities and deaths associated to T2D. Therefore, we have analyzed the role of EMP at the central level in a complex mouse model of AD-T2D. Methods: We have treated AD-T2D mice (APP/PS1xdb/db mice) with EMP 10 mg/kg for 22 weeks. Glucose, insulin, and body weight were monthly assessed. We analyzed learning and memory in the Morris water maze and the new object discrimination test. Postmortem brain assessment was conducted to measure brain atrophy, senile plaques, and amyloid-β levels. Tau phosphorylation, hemorrhage burden, and microglia were also measured in the brain after EMP treatment. Results: EMP treatment helped to maintain insulin levels in diabetic mice. At the central level, EMP limited cortical thinning and reduced neuronal loss in treated mice. Hemorrhage and microglia burdens were also reduced in EMPtreated mice. Senile plaque burden was lower, and these effects were accompanied by an amelioration of cognitive deficits in APP/PS1xdb/db mice. Conclusions: Altogether, our data support a feasible role for EMP to reduce brain complications associated to AD and T2D, including classical pathological features and vascular disease, and supporting further assessment of EMP at the central level.

Liraglutide improved the cognitive function of diabetic mice via the receptor of advanced glycation end products down-regulation

“…Hyperglycemia is one of the most important risk factor of cognition dysfunction in human [ 1 , 2 ] and animal models [ 35 , 36 ] with diabetes mellitus. Therefore, we used db/db mice to explore further confirm the conclusion and probe the effect of liraglutide, a plasma glucose lowing-drug on cognitive function of diabetic mice.…”

Empagliflozin Regulates the AdipoR1/p-AMPK/p-ACC Pathway to Alleviate Lipid Deposition in Diabetic Nephropathy

“…Additionally, empagliflozin improves cardiac function in individuals with diabetes, with improvement in most of the organs under empagliflozin intervention. 20–23 Therefore, in this study, we investigated the effect of empagliflozin among SGLT2is on lipid metabolism in DN.…”

Perspective of SGLT2 Inhibition in Treatment of Conditions Connected to Neuronal Loss: Focus on Alzheimer’s Disease and Ischemia-Related Brain Injury

“…Recent studies suggest that SGLT inhibition may have some impact on the process. Hierro-Bujalance et al [ 25 ], in the first of its kind study regarding SGLT2 inhibitor—empagliflozin (EMP) reportedly reduced senile plaque density and overall reduction of soluble and insoluble amyloid β (Aβ) levels in the cortex and hippocampus of EMP-treated mice of APP/PS1xd/db model. In APP/PS1xd/db mice, brain atrophy is observed as the disease progresses, making the model resembling actual AD pathology.…”

“…What is more, authors reported beneficial effect regarding cognitive function in new object discrimination task and Morris water maze testing where EMP treatment positively affected cognitive abilities of APP/PS1xdb/db mice and significantly ameliorated memory impairment. The researchers could not exclude the leptin signaling alteration as a cause of improvement [ 25 ]. In the work of Lin et al [ 10 ], empagliflozin significantly prevented cognitive function impairment in db/db mice, which was associated with the attenuation of cerebral oxidative stress and the increase in cerebral brain-derived neurotrophic factor (BDNF).…”