Defective Lipoprotein Binding in the Brain Linked to Alzheimer's Disease Risk

Mutations in the TREM2 (Triggering receptor expressed on myeloid cells 2) gene, which encodes a protein expressed selectively by microglia in the brain, have been linked to disrupted binding of lipoproteins and are associated with the development of Alzheimer’s disease (AD).

Previous studies had shown that microglia - immune cells that remove pathogenic materials from the brain in a manner similar to that of microphages in the immune system - from individuals with TREM2 mutations had decreased ability to bind to lipoproteins in the brain's extracellular milieu.

To study this phenomenon further, investigators at the biotech company Genetech (South San Francisco, CA, USA) performed a large unbiased screen of an extracellular recombinant protein library representing 1,559 extracellular proteins and identified a set of lipoprotein particles and apolipoproteins as ligands of TREM2.

They reported in the July 20, 2016, issue of the journal Neuron that the TREM2 ligands included the apolipoproteins APOE and CLU (APOJ), which are risk genes for AD, and that their binding was impaired by TREM2 mutations that conferred AD risk. Binding of these ligands by TREM2 was abolished or reduced by disease-associated mutations.

Overexpression of wild-type TREM2 was sufficient to enhance uptake of LDL, CLU, and APOE in heterologous cells, whereas TREM2 disease variants were impaired in this activity. Amyloid-beta was found to be bound to lipoproteins, and this complex was efficiently taken up by microglia in a TREM2-dependent fashion. Uptake of Amyloid-beta-lipoprotein complexes was reduced in macrophages from human subjects carrying a TREM2 AD variant. In addition, the investigators provided evidence that, through its interaction with lipoproteins, TREM2 could facilitate Amyloid-beta uptake by microglia and human macrophages.

"I think we are only scratching the surface of what TREM2 does," said senior author Dr. Morgan Sheng, vice-president of neuroscience at Genentech. "Lipoproteins float around in the blood, and their purpose is to carry cholesterol or lipids from one cell to another - as we all know, too much LDL is associated with high cholesterol and increased risk of cardiovascular disease. Lipoproteins also exist in the brain, but less is understood about their role there. "

"Overall, these studies further point towards microglia as playing an important role in the pathogenesis of Alzheimer's disease," said Dr. Shen. "It was a surprise that amyloid-beta was much more efficiently engulfed when bound in a lipoprotein complex, rather than when amyloid-beta aggregates were free and naked."

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