Abstract
Metabolic syndrome (MetS) is a cluster of risk factors that lead to microvascular dysfunction and chronic cerebral hypoperfusion (CCH). Long-standing reduction in oxygen and energy supply leads to brain hypoxia and protein misfolding, thereby linking CCH to Alzheimer's disease. Protein misfolding results in neurodegeneration as revealed by studying different experimental models of CCH. Regulating proteostasis network through pathways like the unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), chaperone-mediated autophagy (CMA), and macroautophagy emerges as a novel target for neuroprotection. Lipoxin A4 methyl ester, baclofen, URB597, N-stearoyl-L-tyrosine, and melatonin may pose potential neuroprotective agents for rebalancing the proteostasis network under CCH. Autophagy is one of the most studied pathways of proteostatic cell response against the decrease in blood supply to the brain though the role of the UPR-specific chaperones and the UPS system in CCH deserves further research. Pharmacotherapy targeting misfolded proteins at different stages in the proteostatic pathway might be promising in treating cognitive impairment following CCH.
Highlights
The energy requirements of the brain are high, and neuronal viability critically depends on cerebral blood flow (CBF) delivery of oxygen and nutrients (Daulatzai, 2017)
We reported carotid damage in another mice model 8 weeks after Metabolic syndrome (MetS) induction (OteroLosada et al, 2013), so time-dependency may vary upon the experimental settings
Increasing evidence shows that protein misfolding is involved in CCHinduced neurodegeneration
Summary
The energy requirements of the brain are high, and neuronal viability critically depends on cerebral blood flow (CBF) delivery of oxygen and nutrients (Daulatzai, 2017). Endothelial cells interact with pericytes, glial cells, and neurons to coordinate functions in a neurovascular unit (NVU) (Hermann and ElAli, 2012). Endothelial dysfunction is typically associated with metabolic syndrome (MetS) (Otero-Losada et al, 2013, 2014), and affects CBF distribution and NVU integrity (McCrimmon et al, 2012) bringing about chronic cerebral hypoperfusion (CCH). Since an adequate protein folding and trafficking in neurons depends on energy supply by CBF (Wang and Kaufman, 2016), protein misfolding might be considered a mechanism linking CCH with AD. Neuroprotection in Metabolic Syndrome portrays a promising neuroprotective approach in AD prevention (Jackrel and Shorter, 2017; Sweeney et al, 2017) in the context of MetS
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