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Neurons exposed to LDL exhibit pathological features of Alzheimer’s disease

The brain processes cholesterol separately from the rest of the body. In healthy situations the cholesterol used in the brain is produced in the brain. The Blood Brain Barrier (BBB) prevents cholesterol circulating in the blood from entering the brain.  In diseased states the barrier can become leaky and cholesterol carrying lipoproteins can enter the brain. 

In Alzheimer’s Disease (AD), changes in the brain occur years before symptoms appear. Early changes are a result of breakdown in the BBB, allowing substances from the blood to enter the brain.  Early effects on the neurons include a disruption of the endosome – lysosome system. This system is involved in basic neuronal functions including growth and repair, modification of proteins, and secretory products. Healthy neurons take up cholesterol that is produced locally by astrocytes through receptor mediated endocytosis. This process will also take up lipoproteins not normally found in the brain, for example Low Density Lipoprotein (LDL) from blood.

Investigators at the University of North Dakota Department of Pharmacology, Physiology and Therapeutics have demonstrated changes in the structure and function of neurons that are exposed to LDL (Kalen Biomedical) in vitro. Using primary rat neurons exposed to LDL or Phosphate Buffered Saline (PBS), several changes in the endolysosomes were observed. The endolysosomes became enlarged, and had increased accumulation of cholesterol and BACE-1, a rate limiting enzyme involved in the production of Amyloid Beta (Aβ).The pH of the endolysosomes also increased. Interestingly the mRNA and protein levels of BACE-1 were not elevated , however the  activity of this enzyme increased in endosomes and lysosomes was markedly increased.

Two hallmarks of AD are the accumulation of Aβ, and changes in the phosphorylation of the protein tau which is linked to the disfunction and mislocalization of this protein. The investigators found increased extracellular levels of Aβ and increased phosphorylated tau. They also found decreased levels of synaptophysin a protein that is associated with synaptic function.

These changes in the structure and function of neurons exposed to LDL are strongly linked to the pathological changes found in Alzheimer’s disease.

“Endolysosome involvement in LDL cholesterol-induced Alzheimer’s disease-like pathology in primary cultured neurons.”

Life Sciences Published on 2012 Dec 10;91(23-24):1159-68. doi: 10.1016/j.lfs.2012.04.039. Epub 2012 May 11.

Liang Hui, Xuesong Chen, Jonathan D. Geiger

Department of Pharmacology, Physiology and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203, USA

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