Dementia currently has no cure and, due to the increased prevalence and associated economic and personal burden of this condition, current research efforts for the development of potential therapies have intensified. Recently, targeting integrins as a strategy to ameliorate dementia and other forms of cognitive impairment has begun to gain traction. Integrins are major bidirectional signaling receptors in mammalian cells, mediating various physiological processes such as cell–cell interaction and cell adhesion, and are also known to bind to the extracellular matrix. In particular, integrins play a critical role in the synaptic transmission of signals, hence their potential contribution to memory formation and significance in cognitive impairment. In this review, we describe the physiological roles that integrins play in the blood–brain barrier (BBB) and in the formation of memories. We also provide a clear overview of how integrins are implicated in BBB disruption following cerebral pathology. Given that vascular contributions to cognitive impairment and dementia and Alzheimer’s’ disease are prominent forms of dementia that involve BBB disruption, as well as chronic inflammation, we present current approaches shown to improve dementia-like conditions with integrins as a central focus. We conclude that integrins are vital in memory formation and that their disruption could lead to various forms of cognitive impairment. While further research to understand the relationships between integrins and memory is needed, we propose that the translational relevance of research efforts in this area could be improved through the use of appropriately aged, comorbid, male and female animals.

Intraluminal monofilament model of middle cerebral artery occlusion (MCAO) is widely adopted for ischemic stroke; and Sprague–Dawley (SD) rats are commonly used rodents for preclinical research. Due to the paucity of information on the appropriate monofilament size for inducing MCAO in SD rats and the importance of including middle-aged models in ischemic stroke studies, we aimed to: (i). determine an appropriate Doccol® monofilament size for middle-aged male SD rats which weighed > 500 g following 24-h transient MCAO survival as well as (ii). demonstrate the optimal Doccol® filament size for middle-aged males (≤ 500 g) and females (273–300 g) while using young adult male SD rats (372–472 g) as control for severity of infarct volume following 7-days post-MCAO. All rats were subjected to 90-min transient MCAO. We show that 0.43 mm Doccol® monofilament size is more appropriate to induce large infarct lesion and optimal functional deficit when compared to 0.45 mm and 0.47 mm at 24 h post-MCAO. Our data on infarct volumes at 7 days post-MCAO as well as the observed weight loss and functional deficits at post-MCAO days 1, 3 and 7 demonstrate that 0.41 mm, 0.37 mm and 0.39 mm are optimal Doccol® filament sizes for middle-aged male (477.3 ± 39.61 g) and female (302.6 ± 26.28 g) as well as young-adult male (362.2 ± 28.38 g) SD rats, respectively.

Objectives The gut-microbiome-brain axis is an underexplored mechanism that may mitigate the development of mild cognitive impairment. The objective of this study was to elucidate the effects of a human-modeled Mediterranean diet (MeDi) and Western diet (WD) on cognitive function and gut microbial composition. We hypothesized that consumption of a MeDi would improve cognitive function and modulate beneficial changes to the gut microbiota compared to the WD. Methods Male Sprague Dawley rats (10 weeks of age) were assigned to a MeDi (n = 10) or WD (n = 9) for 3 months. The radial arm water maze (RAWM) was used to assess aspects of short- and long-term memory using discrete error types (working and reference). Data were analyzed using a Two-Way Repeated Measures ANOVA including diet and period. Microbial composition was determined by 16S rRNA sequencing and analyzed using Linear discriminant analysis effect size (LEfSe). Simple linear regression was used to test if the significantly different genera predicted average total error scores. Results Animals consuming the MeDi committed fewer reference memory (p = 0.02), working memory incorrect (p = 0.04), and total errors (p = 0.01), and had a trend toward fewer working memory correct errors (p = 0.08) compared to the WD. MeDi gut microbiota composition was distinct (p < 0.001) and had a trend to be move diverse (Shannon, p = 0.05; Simpson, p = 0.05; Chao1, p = 0.06) compared to the WD. LEfSe analysis revealed 9 differentially abundant genera between the MeDi and WD. The MeDi had an increased abundance of 6 genera including Lachnoclostridium (p < 0.001), Candidatus Saccharimonas (p < 0.001), and Romboutsia (p = 0.01). Decreased abundances in the MeDi group included Bifidobacterium (p < 0.001) and Erysipelatoclostridium (p = 0.003). It was found that Candidatus Saccharimonas (p = 0.02, r2 = 0.31, β = 0.007), Romboutsia (p = 0.03, r2 = 0.25, β = 0.033), and Bifidobacterium (p = 0.01, r2 = 0.35, β = −0.118) significantly predicted total errors. Conclusions Relative to animals consuming the WD, the MeDi enhanced short- and long-term memory and differentially abundant genus level bacteria were predictive of memory outcomes. The MeDi may maintain cognitive function through modulation of the gut microbiota. Funding Sources None.

Patients with significant cerebrovascular comorbidities (e.g. brain ischemia, vascular dementia) are more affected and are more likely to have worsened post-acute neurologic sequelae after SARS-CoV-2 infection. This may be due to viral invasion and propagation in brain endothelial cells (BECs) and disruption of the blood-brain barrier (BBB). Viral spike protein used to bind and infect host cells encodes an arginine-glycine-aspartic acid (RGD) motif that it may use to bind integrins cell receptors that play an important role in cerebrovascular integrity. Therefore, integrins may represent an acute and post-acute SARS-CoV-2 therapeutic target. However, the interplay between vascular dysregulation, integrin function, and COVID-19 is unclear. As we have previously demonstrated that activation of the integrin α5 plays a key role in BBB breakdown, stroke injury, OGD/R, SARS-CoV-2 infection, and its inhibition with the clinically validated peptide ATN-161 is therapeutic in these conditions, we hypothesize that SARS-CoV-2 alters BEC α5 integrin (and associated tight junction protein) expression as a means of infecting and altering cerebrovascular integrity, and this can be prevented by ATN-161. Methods: Mouse BECs (bEnd3) were inoculated with heat-inactivated SARS-CoV-2 (Isolate USA-WA1/2020) or delta variant of SARS-CoV-2 spike protein for 24 h then later exposed to hypoxia for 6h to model the effects of in vivo pulmonary infection. Cells were pretreated with ATN-161 (1, 5, and 10μM) 1h before SARS-CoV-2 challenge and during hypoxia. α5 and claudin-5 proteins were analyzed by immunoblotting. Results: Both SARS-CoV-2 inoculations induced integrin α5 and decreased claudin-5 expression (delta > SARS-CoV-2) in a dose-dependent fashion, although higher doses of SARS-CoV-2 (2.5 and 5 μg) had no effect on these proteins. SARS-CoV-2 spike protein challenge at 0.5 μg followed by hypoxia resulted in increased α5 and decreased claudin-5 expression in either hypoxia or SARS-CoV-2+hypoxia combination. ATN-161 (10μM) pretreatment inhibited SARS-CoV-2+hypoxia-induced α5 upregulation and restored claudin-5 loss. In addition to its demonstrated anti-viral effects, ATN-161 may be an important therapy for SARS-CoV-2-mediated cerebrovascular injury.

BackgroundAlterations in the gut microbiota have been observed in patients with mild cognitive impairment and Alzheimer’s disease. Dietary consumption directly modulates gut microbiota; therefore, the quality of a diet may impact cognitive function and susceptibility to dementia. We hypothesized that consumption of the nutrient dense Mediterranean diet (MeDi) would improve cognitive function through beneficial changes to the gut microbiota as compared to the diet primarily consumed by Americans, the Western diet (WD).MethodTen‐week‐old Sprague Dawley male rats were assigned a MeDi (n = 10) or WD (n = 9). After three months, Morris water maze (MWM) was used to assess spatial reference memory cognition. MWM data were analyzed with two‐way RM ANOVA. Fecal samples were collected prior to the MWM. Microbial composition was determined by 16S rRNA sequencing, and analyses included Mann‐Whitney with false discovery rate.ResultThe MeDi group also spent significantly more time in the target quadrant during probe testing (p = 0.03) and was quicker to reach the platform on reversal testing (p = 0.004), indicative of improved cognitive flexibility. Microbiota α‐diversity indices, Shannon (p = 0.053), Simpson (p = 0.054), and Chao1 (p = 0.056), had a trend to be increased in the MeDi. Microbiota β‐diversity was dissimilar between diets (p<0.001). At the phylum level, Actinobacteria decreased and Patescibacteria increased with consumption of the MeDi as compared to the WD. Actinobacteria relative abundance correlated with MWM time in target quadrant (r = ‐0.58, p = 0.009). Further, relative abundance of Actinobacteria and Patescibacteria correlated with MWM reversal distance to reach platform (Actinobacteria, r = 0.77, p = 0.0001; Patescibacteria, r = ‐0.59, p = 0.007).ConclusionThe MeDi maintained long‐term spatial memory, as measured by the MWM, compared to the WD. Additionally, diet‐modulated gut microbiota at the phylum level and these changes were correlated with cognitive function. Modulation of the gut microbiota through a neuroprotective diet, such as the MeDi, may serve as a method to improve cognitive function.