Relationship between Brain Metabolic Disorders and Cognitive Impairment: LDL Receptor Defect

Abstract

The low-density-lipoprotein receptor (LDLr) removes low-density lipoprotein (LDL), an endovascular transporter that carries cholesterol from the bloodstream to peripheral tissues. The maintenance of cholesterol content in the brain, which is important to protect brain function, is affected by LDLr. LDLr co-localizes with the insulin receptor and complements the internalization of LDL. In LDLr deficiency, LDL blood levels and insulin resistance increase, leading to abnormal cholesterol control and cognitive deficits in atherosclerosis. Defects in brain cholesterol metabolism lead to neuroinflammation and blood-brain-barrier (BBB) degradation. Moreover, interactions between endoplasmic reticulum stress (ER stress) and mitochondria are induced by ox-LDL accumulation, apolipoprotein E (ApoE) regulates the levels of amyloid beta (Aβ) in the brain, and hypoxia is induced by apoptosis induced by the LDLr defect. This review summarizes the association between neurodegenerative brain disease and typical cognitive deficits.

Keywords: ER stress; LDLr; SREBP; apoptosis; blood–brain-barrier (BBB) breakdown; cholesterol metabolism; insulin receptor; lectin-like oxidized LDL receptor-1 (LOX-1); mitochondria; neuroinflammation.

Figure 1

Interaction of low-density-lipoprotein receptor (LDLr) and insulin receptor (IR). The process of the expression of LDLr and endocytosed downstream molecules to regulate cholesterol homeostasis and the association of co-localized IR.

Figure 2

Blood–brain-barrier (BBB) breakdown due to inflammation. BBB breakdown process induced by NLRP3-mediated inflammation.

Figure 3

Interaction between ER stress and mitochondria. The process by which ER stress and mitochondria interact due to oxLDL accumulation due to LDLr deficiency affects cognitive impairment.

Figure 4

The process of the clearance of ApoE/Aβ complexes by LDLr.