Abstract
BackgroundDiabetes mellitus (DM) and chronic cerebral hypoperfusion(CCH)are both risk factors for cognitive impairment. However, whether DM and CCH can synergistically promote cognitive impairment and the related pathological mechanisms remain unknown.MethodsTo investigate the effect of DM and CCH on cognitive function, rats fed with high-fat diet (HFD) and injected with low-dose streptozotocin (STZ) followed by bilateral common carotid artery occlusion (BCCAO) were induced to mimic DM and CCH in vivo and mouse BV2 microglial cells were exposed to hypoxia and/or high glucose to mimic CCH complicated with DM pathologies in vitro. To further explore the underlying mechanism, TREM-2-specific small interfering RNA and TREM-2 overexpression lentivirus were used to knock out and overexpress TREM-2, respectively.ResultsCognitive deficits, neuronal cell death, neuroinflammation with microglial activation, and TREM-2-MAPK signaling were enhanced when DM was superimposed on CCH both in vivo and in vitro. Manipulating TREM-2 expression levels markedly regulated the p38 MAPK signaling and the inflammatory response in vitro. TREM-2 knockout intensified while TREM-2 overexpression suppressed the p38 MAPK signaling and subsequent pro-inflammatory mediator production under high glucose and hypoxia condition.ConclusionsThese results suggest that TREM-2 negatively regulates p38 MAPK-mediated inflammatory response when DM was synergistically superimposed on CCH and highlight the importance of TREM-2 as a potential target of immune regulation in DM and CCH.
Highlights
As the second most common form of dementia, vascular dementia (VaD) is mainly caused by chronic cerebral hypoperfusion (CCH), which is an aging-related process characterized by a persistent reduction of cerebral blood flow (CBF) [1, 2]
Stable models of Diabetes mellitus (DM) and CCH were successfully established in vivo and in vitro In order to better mimic the clinical characteristics of diabetic patients who suffered from chronic cerebral hypoperfusion, a rat model of DM and CCH was developed in vivo
These results demonstrate that rats treated with high-fat diet (HFD)-STZ and bilateral common carotid artery occlusion (BCCAO) showed clinical characteristics of type 2 diabetes (T2DM) and CCH
Summary
As the second most common form of dementia, vascular dementia (VaD) is mainly caused by chronic cerebral hypoperfusion (CCH), which is an aging-related process characterized by a persistent reduction of cerebral blood flow (CBF) [1, 2]. Multiple vascular comorbidities, such as obesity and diabetes, can accelerate the reduction of CBF and facilitate the onset and progression of cognitive impairment [3, 4]. Whether DM and CCH can synergistically promote cognitive impairment and the related pathological mechanisms remain unknown
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