HMGB1/RAGE/TLR4 axis and glutamate as novel targets for PCSK9 inhibitor in high fat cholesterol diet induced cognitive impairment and amyloidosis

Alzheimer's disease (AD) is a leading health problem in which increased amyloid β (Aβ) accumulation may occur due to abnormal Aβ precursor protein processing by β-secretase 1 (BACE1) enzyme. Lately, neuro-inflammation was recognized as a significant contributor to its pathogenesis. Although the causes of AD are not yet well understood, much evidence has suggested that dyslipidemia has harmful effects on cognitive function and is inextricably involved in AD pathogenesis. Cholesterol is a vital molecule involved in neuronal development. Alteration in neuronal cholesterol levels affects Aβ metabolism and results in neurodegeneration. Proprotein-convertase-subtilisin/kexin type-9 (PCSK9) was found to decrease neuronal cholesterol uptake by degradation of LDL-receptor related protein 1 (LRP-1) responsible for neuronal cholesterol uptake. Accordingly, this study was designed to evaluate the effect of PCSK9-inhibition by alirocumab (Aliro) in high-fat-cholesterol-diet (HFCD)-induced-AD-like condition. Wistar Rats were divided into six groups; control; HFCD; HFCD and Memantine; HFCD and Aliro (4, 8 and 16 mg/kg/week) to test for ability of Aliro to modulate cognitive impairment, amyloidosis, brain cholesterol homeostasis and neuro-inflammation in HFCD-induced-AD-like condition. Our results demonstrated an association between PCSK9 inhibition by Aliro and amelioration of cognitive deficit, cholesterol hemostasis and reduction of neuro-inflammation. Aliro was able to alleviate hippocampal LRP-1expression levels and reduce brain cholesterol, hippocampal BACE1, Aβ42, high-mobility-group-box-1 protein, receptor for advanced-glycation-end-products and toll like receptor-4 with subsequent decrease of different inflammatory mediators as nuclear-factor-kappa-B (NF-κB), tumor-necrosis-factor-alpha (TNF-α), interleukin-1beta (IL-1β) and IL-6. PCSK9-inhibition may represent a new therapeutic target in AD especially for HFCD-induced-AD-like condition.