**Abstract**

Metabolic syndrome (MetS) leads to microvascular dysfunction and chronic cerebral hypoperfusion (CCH) in an insidious way. Clinical evidence and several rodent models have contributed to determining the neurodegenerative effect of a sustained decrease in cerebral blood flow (CBF). Protein misfolding and aggregation derived from CCH might account for the establishment of vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). However, the complex and multifactorial etiology of cerebrovascular disease demands the combination of experimental models in scientific research. In this sense, the present work aims at summarizing the differential available rodent paradigms for studying the establishment of cognitive decline resulting from protein misfolding induced by MetS in association with CCH. Revising experimental findings in the field will help further basic research on the pathophysiology of cerebrovascular disease and the future testing of protein-remodeling factors as neuroprotective agents for the prevention of cognitive impairment.

**Keywords:** metabolic syndrome (MetS), chronic cerebral hypoperfusion (CCH), protein misfolding, experimental models, cognitive impairment

## **1. Introduction**

Metabolic syndrome (MetS) is the resulting condition of specific concurrent maladies, whose common pathogenic component is insulin resistance. Difficult to diagnose in clinical practice, there is consensus on its presence provided a cluster of risk factors be present, including abdominal obesity, hyperglycemia, hypertriglyceridemia, and hypertension [1–3]. Several murine models have contributed to the knowledge of this vascular risk factors' constellation, which has been studied for over 80 years [4]. The experimental evidence shows that MetS silently, though relentlessly, leads to microvascular dysfunction and chronic cerebral hypoperfusion (CCH) [5]. Clinical findings, including the multivariate association between functional microvascular variables and laboratory-anthropometrical measurements [6], have reinforced the linkage of MetS with CCH [7], which leads to cognitive decline in late middle-aged adults [8]. As much as CCH might explain the considerable overlap between features of vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD), it might also underly as a common pathophysiological mechanism [9]. Experimental models of CCH have also contributed to exploring the interplay between hypoperfusion and amyloid β (Aβ) deposition, as it relates to AD [9]. Scientific evidence has underscored the importance of treating dementia comorbid disease conditions, including hypometabolism and diminished cerebral blood flow (CBF) [10]. An alternative target in neuroprotection is the regulation of the proteostasis network since protein aggregates link MetS-induced CCH and sporadic AD late-onset [11]. Therefore, the present work aims at revising different murine models of MetS and CCH, summarizing those experimental findings of relevance in the establishment of cerebrovascular disease. Plus, this overview intends to shed light on the usefulness of experimental models for the study of protein misfolding as a mechanism of neurodegeneration in CCH. Thirdly, this review attempts to discuss the requirement of combining MetS and CCH experimental models in order to resemble multifactorial conditions like VCID and AD and to test protein-remodeling factors as potential neuroprotective mechanisms for cognitive decline in the aging brain [12].
