<h3>Title</h3>
<h3>Soluble TREM2 inhibits secondary nucleation of Aβ fibrillization and enhances cellular uptake of fibrillar Aβ</h3>
<p><strong><span style="text-decoration: underline;">Abstract</span> :</strong></p>
<p>Proteins and enzymes are basic biomolecules and are the major structural and functional element of a cell. Mutations in cellular proteins result in changes in their functionality due to either loss of function or toxic gain of function.<br />In the first talk, I will describe a protein- Triggering receptor expressed on myeloid cells 2 (TREM2) which is a single-pass transmembrane receptor of the immunoglobulin superfamily that is secreted in a soluble (sTREM2) form. Mutations in TREM2 have been linked to increased risk of Alzheimer’s disease (AD). A prominent neuropathological component of AD is deposition of the amyloid beta (Aβ) into plaques, particularly Aβ40 and Aβ42. While the membrane-bound form of TREM2 is known to facilitate uptake of Aβ fibrils and the polarization of microglial processes toward amyloid plaques, the role of its soluble ectodomain, particularly in interactions with monomeric or fibrillar Aβ has been less clear. Using biophysical studies and biochemical &amp; cellular assays, we probed the interaction of sTREM2 and Aβ. Kinetic analysis shows that sTREM2 inhibits the secondary nucleation step in the fibrillization of Aβ, while having little effect on the primary nucleation pathway. Furthermore, binding of sTREM2 to fibrils markedly enhanced uptake of fibrils into human microglial and neuroglioma derived cell lines. The disease-associated<br />sTREM2 mutant, R47H, displayed little to no effect on fibril nucleation and binding, but it decreased uptake and functional responses markedly. Finally, I will describe the structure of the WT sTREM2–Aβ fibril complex using integrative molecular modeling based primarily on the cross- linking mass spectrometry data. The model shows that sTREM2 binds fibrils along one face of the structure, leaving a second, mutation-sensitive site free to mediate cellular binding and uptake.</p>