Amyloid-beta impairs insulin signaling by accelerating autophagy-lysosomal degradation of LRP-1 and IR-β in blood-brain barrier endothelial cells in vitro and in 3XTg-AD mice

Abstract

Aberrant insulin signaling constitutes an early change in Alzheimer's disease (AD). Insulin receptors (IR) and low-density lipoprotein receptor-related protein-1 (LRP-1) are expressed in brain capillary endothelial cells (BCEC) forming the blood-brain barrier (BBB). There, insulin may regulate the function of LRP-1 in Aβ clearance from the brain. Changes in IR-β and LRP-1 and insulin signaling at the BBB in AD are not well understood. Herein, we identified a reduction in cerebral and cerebrovascular IR-β levels in 9-month-old male and female 3XTg-AD (PS1M146V, APPSwe, and tauP301L) as compared to NTg mice, which is important in insulin mediated signaling responses. Reduced cerebral IR-β levels corresponded to impaired insulin signaling and LRP-1 levels in brain. Reduced cerebral and cerebrovascular IR-β and LRP-1 levels in 3XTg-AD mice correlated with elevated levels of autophagy marker LC3B. In both genotypes, high-fat diet (HFD) feeding decreased cerebral and hepatic LRP-1 expression and elevated cerebral Aβ burden without affecting cerebrovascular LRP-1 and IR-β levels. In vitro studies using primary porcine (p)BCEC revealed that Aβ peptides 1–40 or 1–42 (240 nM) reduced cellular levels and interaction of LRP-1 and IR-β thereby perturbing insulin-mediated signaling. Further mechanistic investigation revealed that Aβ treatment accelerated the autophagy-lysosomal degradation of IR-β and LRP-1 in pBCEC. LRP-1 silencing in pBCEC decreased IR-β levels through post-translational pathways further deteriorating insulin-mediated responses at the BBB. Our findings indicate that LRP-1 proves important for insulin signaling at the BBB. Cerebral Aβ burden in AD may accelerate LRP-1 and IR-β degradation in BCEC thereby contributing to impaired cerebral and cerebromicrovascular insulin effects.

β‑asarone modulates Beclin‑1, LC3 and p62 expression to attenuate Aβ40 and Aβ42 levels in APP/PS1 transgenic mice with Alzheimer's disease

“…aβ 1-42 serves a vital role in the pathogenesis of ad owing to its strong aggregative ability and neurotoxicity (2). autophagy can protect against ad by clearing aβ deposition and preserving neuronal function (7). Furthermore, autophagic activity increases when cells experience injury, nutritional deficiency, growth factor deficits or high energy demand (4).…”

“…Previous studies have reported that autophagy may be involved in ad pathogenesis (6). in addition, autophagy serves an important role in clearing aβ aggregation and preserving neuronal function in ad (7). another recent study also indicated that aβ 1-42 can induce autophagic cell death and autophagic vacuoles (8).…”

A Fundamental Role for Oxidants and Intracellular Calcium Signals in Alzheimer’s Pathogenesis—And How a Comprehensive Antioxidant Strategy May Aid Prevention of This Disorder

“…Amyloid β oligomers act on brain capillary cells to suppress expression of both LRP1 and of P-glycoprotein (P-GP); LRP1 acts in the abluminal capillary membrane to extract amyloid β monomers/oligomers from the brain extracellular space, and P-G acts on the luminal side to expel them into the circulation [ 177 , 178 , 179 , 180 , 181 , 182 , 183 ]. Hence, they act in tandem to expel intact amyloid beta from the brain.…”

Western Diet Induces Impairment of Liver-Brain Axis Accelerating Neuroinflammation and Amyloid Pathology in Alzheimer's Disease

“…In particular, Aβ level in the brain depends on the continuous control of Aβ influx and efflux via receptors RAGE and LRP1 located at the BBB (Zlokovic et al, 2010 ). Intake of diets high in SFAs, cholesterol and carbohydrates increases levels of circulating Aβ, disturbs its peripheral clearance by the liver and impairs brain Aβ clearance and efflux by decreased LRP1 and increased RAGE protein expression or activity (Kim et al, 2016 ; Gali et al, 2019 ). In turn, BBB dysfunction triggers oxidative stress and neuroinflammation, which causes enhancement of the activity of β-secretase and γ-secretase promoting generation of a new portion of Aβ peptides (Cai et al, 2018 ).…”