Combination treatment with cilostazol and isosorbide mononitrate attenuates microemboli-mediated vascular cognitive impairment and improves imaging and plasma biomarkers in diabetic rats.

Diabetes is a major risk factor for all types of dementia. The underlying reasons are not fully understood, and preventive therapeutic strategies are lacking. Previously we have shown that diabetic but not control rats developed a progressive cognitive decline in a microemboli (ME) model of vascular contributions to cognitive impairment & dementia (VCID).

Complex regulation of tau phosphorylation by the endothelin system in brain microvascular endothelial cells (BMVECs): link to barrier function.

Endothelin-1 (ET-1), the most potent vasoconstrictor identified to date, contributes to cerebrovascular dysfunction. ET-1 levels in postmortem brain specimens from individuals diagnosed with Alzheimer's disease (AD) and related dementias (ADRD) were shown to be related to cerebral hypoxia and disease severity. ET-1-mediated vascular dysfunction and ensuing cognitive deficits have also been reported in experimental models of AD and ADRD.

p17/C18-ceramide-mediated mitophagy is an endogenous neuroprotective response in preclinical and clinical brain injury.

Repeat concussions (or repetitive mild traumatic brain injury [rmTBI]) are complex pathological processes consisting of a primary insult and long-term secondary complications and are also a prerequisite for chronic traumatic encephalopathy (CTE). Recent evidence implies a significant role of autophagy-mediated dysfunctional mitochondrial clearance, mitophagy, in the cascade of secondary deleterious events resulting from TBI. C18-ceramide, a bioactive sphingolipid produced in response to cell stress and damage, and its synthesizing enzyme (CerS1) are precursors to selective stress-mediated mitophagy.

Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects.

The metabolic consequences of mitophagy alterations due to age-related stress in healthy aging brains versus neurodegeneration remain unknown. Here, we demonstrate that ceramide synthase 1 (CerS1) is transported to the outer mitochondrial membrane by the p17/PERMIT transporter that recognizes mislocalized mitochondrial ribosomes (mitoribosomes) via 39-FLRN-42 residues, inducing ceramide-mediated mitophagy. P17/PERMIT-CerS1-mediated mitophagy attenuated the argininosuccinate/fumarate/malate axis and induced d-glucose and fructose accumulation in neurons in culture and brain tissues (primarily in the cerebellum) of wild-type mice in vivo.

Endothelin A receptors contribute to senescence of brain microvascular endothelial cells.

Cellular senescence plays a pivotal role in the aging and progression of neurodegenerative diseases, including vascular cognitive impairment and dementia (VCID). In postmortem brains from individuals with VCID, endothelin-1 (ET-1) levels closely correlate with blood barrier breakdown and cerebral hypoperfusion. Brain microvascular endothelial cells (BMVECs), previously thought to have exclusively endothelin B receptors, also possess endothelin A (ETA) receptors; however, the functional significance of this receptor in BMVECs is not known.

infection upregulates the endothelin (ET) system in brain microvascular endothelial cells.

Endothelin-1 (ET-1), the most potent vasoconstrictor identified to date, contributes to cerebrovascular dysfunction and brain ET-1 levels were shown to be related to Alzheimer's disease and related dementias (ADRD) progression. ET-1 also contributes to neuroinflammation, especially in infections of the central nervous system. Recent studies causally linked chronic periodontal infection with an opportunistic anaerobic bacterium (Coykendall et al.

Endocannabinoid Signaling for GABAergic-Microglia (Mis)Communication in the Brain Aging.

The aging brain seems to be characterized by neuronal loss leading to cognitive decline and progressively worsening symptoms related to neurodegeneration. Also, pro-inflammatory states, if prolonged, may increase neuronal vulnerability via excessive activation of microglia and their pro-inflammatory by-products, which is seen as individuals increase in age. Consequently, microglial activity is tightly regulated by neuron-microglia communications.