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Central response to insulin is suspected to be defective in Alzheimer’s disease (AD), but its localization in the brain remains unknown. While most insulin is secreted in the bloodstream by the pancreas, how it interacts with the blood-brain barrier (BBB) to alter brain function remains poorly defined.Here, we show that human and murine cerebral insulin receptors (INSR), particularly the long isoform INSRα-B, are concentrated in microvessels rather than in the parenchyma. Vascular concentrations of INSRα-B were lower in the parietal cortex of subjects diagnosed with AD, positively correlating with cognitive scores, leading to a shift toward a higher INSRα-A/B ratio, consistent with cerebrovascular insulin resistance in the AD brain. Vascular INSRα was inversely correlated with β-amyloid (Aβ) plaques and β-site APP cleaving enzyme 1 (BACE1), but positively correlated with insulin-degrading enzyme (IDE), neprilysin and ABCB1. Using brain cerebral intracarotid perfusion, we found that the transport rate of insulin across the BBB remained very low (-1.s-1) and was not inhibited by an INSR antagonist. However, intracarotid perfusion of insulin induced the phosphorylation of INSRβ which was restricted to microvessels. Such an activation of vascular INSR was blunted in 3xTg-AD mice, suggesting that AD neuropathology induces insulin resistance at the level of the BBB.Overall, the present data in postmortem AD brains and an animal model of AD indicate that defects in the INSR localized at the BBB strongly contribute to brain insulin resistance in AD, in association with Aβ pathology.HighlightsCirculating insulin activates brain insulin receptors in microvessels.BBB INSR contribute to cerebral insulin resistance in AD.Cognitive impairment in AD is associated with a loss of cerebrovascular INSRα-B.Loss of isoform INSRα-B is associated with increased BACE1 activity.SummaryLeclerc et al. show that circulating insulin activates cerebral insulin receptor localized on the blood-brain-barrier level (BBB), not in the parenchyma. Experiments with human brain samples and animal models provide evidence that INSR at the BBB are impaired in Alzheimer’s disease, thereby contributing to brain insulin resistance.

BACKGROUND Vitamin A (VitA), via its active metabolite retinoic acid (RA), is critical for the maintenance of memory function with advancing age. Although its role in Alzheimer's disease (AD) is not well understood, data suggest that impaired brain VitA signaling is associated with the accumulation of ��-amyloid peptides (A��), and could thus contribute to the onset of AD. METHODS We evaluated the protective action of a six-month-long dietary VitA-supplementation (20��IU/g), starting at 8��months of age, on the memory and the neuropathology of the 3xTg-AD mouse model of AD (n��=��11-14/group; including 4-6 females and 7-8 males). We also measured protein levels of Retinoic Acid Receptor �� (RAR��) and Retinoid X Receptor �� (RXR��) in homogenates from the inferior parietal cortex of 60 participants of the Religious Orders study (ROS) divided in three groups: no cognitive impairment (NCI) (n��=��20), mild cognitive impairment (MCI) (n��=��20) and AD (n��=��20). RESULTS The VitA-enriched diet preserved spatial memory of 3xTg-AD mice in the Y maze. VitA-supplementation affected hippocampal RXR expression in an opposite way according to sex by tending to increase in males and decrease in females their mRNA expression. VitA-enriched diet also reduced the amount of hippocampal A��40 and A��42, as well as the phosphorylation of tau protein at sites Ser396/Ser404 (PHF-1) in males. VitA-supplementation had no effect on tau phosphorylation in females but worsened their hippocampal A�� load. However, the expression of Rxr-�� in the hippocampus was negatively correlated with the amount of both soluble and insoluble A�� in both males and females. Western immunoblotting in the human cortical samples of the ROS study did not reveal differences in RAR�� levels. However, it evidenced a switch from a 60-kDa-RXR�� to a 55-kDa-RXR�� in AD, correlating with ante mortem cognitive decline and the accumulation of neuritic plaques in the brain cortex. CONCLUSION Our data suggest that (i) an altered expression of RXRs receptors is a contributor to ��-amyloid pathology in both humans and 3xTg-AD mice, (ii) a chronic exposure of 3xTg-AD mice to a VitA-enriched diet may be protective in males, but not in females.

Alzheimer's disease (AD) is a complex age-related neurodegenerative disease, associated with central and peripheral metabolic anomalies, such as impaired glucose utilization and insulin resistance. These observations led to a considerable interest not only in lifestyle-related interventions, but also in repurposing insulin and other anti-diabetic drugs to prevent or treat dementia. Body temperature is the oldest known metabolic readout and mechanisms underlying its maintenance fail in the elderly, when the incidence of AD rises. This raises the possibility that an age-associated thermoregulatory deficit contributes to energy failure underlying AD pathogenesis. Brown adipose tissue (BAT) plays a central role in thermogenesis and maintenance of body temperature. In recent years, the modulation of BAT activity has been increasingly demonstrated to regulate energy expenditure, insulin sensitivity and glucose utilization, which could also provide benefits for AD. Here, we review the evidence linking thermoregulation, BAT and insulin-related metabolic defects with AD, and we propose mechanisms through which correcting thermoregulatory impairments could slow the progression and delay the onset of AD.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major cause of death in the elderly. Cognitive decline due to Alzheimer's disease (AD) is frequent in the geriatric population disproportionately affected by the COVID-19 pandemic. Interestingly, central nervous system (CNS) manifestations have been reported in SARS-CoV-2-infected patients. In this study, we investigated the levels of Angiotensin I Converting Enzyme 2 (ACE2), the main entry receptor of SARS-COV-2 in cells, in postmortem parietal cortex samples from two independent AD cohorts, totalling 142 persons. Higher concentrations of ACE2 protein and mRNA were found in individuals with a neuropathological diagnosis of AD compared to age-matched healthy control subjects. Brain levels of soluble ACE2 were inversely associated with cognitive scores (p = 0.02), markers of pericytes (PDGFRβ, p=0.02 and ANPEP, p = 0.007) and caveolin1 (p = 0.03), but positively correlated with soluble amyloid-β peptides (Aβ) concentrations (p = 0.01) and insoluble phospho- tau (S396/404, p = 0.002). No significant differences in ACE2 were observed in the 3xTgAD mouse model of tau and Aβ neuropathology. Results from immunofluorescence and Western blots showed that ACE2 protein is mainly localized in neurons in the human brain but predominantly in microvessels in the mouse brain. The present data show that an AD diagnosis is associated with higher levels of soluble ACE2 in the human brain, which might contribute to a higher risk of CNS SARS-CoV-2 infection.