**Background:** Metabolic syndrome (MetS) and type 2 diabetes (T2D) are established risk factors for chronic cerebral hypoperfusion (CCH) and subsequent neurodegeneration, including Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID). The coexistence of atherogenic dyslipidemia, hypertension, hyperglycemia, a prothrombotic state, and a proinflammatory state in MetS creates a particularly risky condition. Chronic subclinical vascular inflammation, driven by abnormal adipocytokine production (e.g., TNF-α, IL-1, IL-6, leptin, adiponectin), leads to atherosclerotic processes. Protein misfolding and aggregation are common pathophysiological features linking MetS, T2D, CCH, and neurodegeneration. This review aims to update the scientific knowledge on single and combined experimental induction of MetS, T2D, and CCH in rodent models, and to summarize the neuroprotective properties of protein-remodeling factors.
**Methods:** This is a narrative review that synthesizes findings from preclinical studies using rodent models. The authors describe various models for MetS (e.g., Obese Zucker rats, Wistar Ottawa Karlsburg W (WOKW) rats, high-fat diet (HFD) models, sweet carbonated beverage models, low-capacity runner (LCR) rats, spontaneously hypertensive rat (SHR) variants), T2D (e.g., leptin-deficient OB/OB mice, leptin receptor-deficient db/db mice, Otsuka Long-Evans Tokushima Fatty Rats (OLETF), streptozotocin (STZ)-induced models, HFD/STZ combination), and CCH (e.g., bilateral common carotid artery occlusion (BCCAO), bilateral common carotid artery stenosis (BCCAS), gradual common carotid artery stenosis). The review discusses evidence on whether MetS or T2D leads to CCH, citing studies that measured cerebral blood flow using techniques such as Doppler optical coherence tomography, angiography, and dynamic contrast-enhanced MRI. It also summarizes recent findings on neuroprotective strategies targeting protein misfolding clearance mechanisms, including the ubiquitin-proteasome system (UPS), chaperone-mediated autophagy (CMA), and macroautophagy.
**Key Results:** The review highlights several key findings from preclinical studies: (1) In Zucker obese (ZO) rats, mitochondrial dysfunction contributes to impaired vasodilation, and lumen reduction in the middle cerebral artery is observed. (2) In db/db diabetic mice combined with common carotid artery occlusion (CCAO), brain perfusion was impaired compared to controls, indicating that T2D increases cerebral hypoperfusion. (3) A cafeteria diet in Sprague Dawley rats produced a MetS phenotype and increased resting cerebral perfusion in the cerebral cortex and hippocampus but decreased cerebrovascular reactivity after 3-4 months. (4) HFD in mice caused endothelial dysfunction of cerebral arterioles after 12 and 36 weeks, and impaired blood flow in unilateral CCAO mice after 6.5 months. (5) Neuroprotective agents targeting proteostasis include: Gastrodin (GAS), which ameliorated learning and memory impairment in a rat model of vascular dementia by promoting autophagy flux via inhibition of the Ca2+/CaMKII signaling pathway; Lipoxin A4 methyl ester (LXA4 ME), which ameliorated hippocampal degeneration in CCH rats by regulating ER stress and macroautophagy; Baclofen, which prevented hippocampal atrophy and neuronal apoptosis by suppressing cytodestructive autophagy via the Akt/ERK-Bcl2-beclin-1 pathway and activating protective autophagy via the GABAA receptor-CX43/CX36 pathway; URB597 (a FAAH inhibitor), which suppressed apoptosis and ameliorated neurodegeneration and cognitive impairment in BCCAO mice via the m-TOR pathway; Melatonin, which modulated CCH-induced stress protein expression and restored HSP70 levels in the hippocampus of BCCAO mice; N-stearoyl-L-tyrosine (NSTyr), which increased proteasome peptidase activity and inhibited intracellular aggregation of ubiquitinated proteins in a rat model; and Palmitoylethanolamide, which reduced alterations in hippocampal MAP-2 levels and reversed behavioral dysfunctions in a murine acute hypoxia model. The review also discusses the WFS1 gene, which is involved in ER Ca2+ homeostasis and the unfolded protein response (UPR). WFS1 deficiency is associated with increased tau pathology and neurodegeneration, while overexpression can reduce these changes, making it a potential therapeutic target for neurodegenerative diseases.
**Clinical Implications:** The association between MetS and CCH may lead to vascular cognitive impairment, but the specific metabolic changes responsible remain to be fully characterized. Promising research into agents that promote proteome homeostasis may ameliorate vascular cognitive dysfunction. Substantial clinical benefits may be achieved by increasing knowledge of cellular pathways involved in degrading pathogenic proteins. Protein-remodeling factors should be assessed as neuroprotective agents for preventing cerebrovascular disease and cognitive decline. While lifestyle and dietary changes are the main approaches to improving MetS, neuroprotective agents can be used simultaneously to prevent disruption of protein synthesis and cell death. Future research should focus on developing proteostatic changes in animal models of MetS and CCH to elucidate mechanisms involved in VCID and AD.