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TMEM97 increases in synapses and is a potential synaptic Aβ binding partner in human Alzheimer's disease

By Marti Colom-Cadena, Jane Tulloch, Rosemary J. Jackson, James H Catterson, Jamie Rose, Caitlin Davies, Monique Hooley, Alejandro Anton-Fernandez, Sophie Dunnett, Robert Tempelaar, Makis Tzioras, Nicholas J Izzo, Susan M Catalano, Colin Smith, Tara Spires-Jones

Posted 01 Feb 2021
bioRxiv DOI: 10.1101/2021.02.01.428238

Synapse loss correlates with cognitive decline in Alzheimer's disease (AD), and soluble amyloid beta (A{beta}) is implicated in synaptic dysfunction and loss. An important knowledge gap is the lack of understanding of how synaptic accumulation of A{beta} leads to synapse degeneration. In particular, there has been difficulty in determining whether there is a synaptic receptor that binds A{beta} and mediates toxicity. While many candidate synaptic binding partners have been observed in model systems, their relevance to human AD brain remains unknown. This is in part due to methodological limitations preventing visualization of A{beta} binding at individual synapses. To overcome this limitation, we combined two high resolution microscopy techniques: array tomography and Forster resonance energy transfer (FRET) to image over 1 million individual synaptic terminals in temporal cortex from AD (n=9) and age matched control cases (n=6). Within postsynaptic densities, A{beta} generates a FRET signal with transmembrane protein 97 (TMEM97), recently discovered to be the Sigma-2 receptor, cellular prion protein, and postsynaptic density 95 (PSD95). TMEM97 is also present in a higher proportion of postsynapses in AD brain compared to control. Further, we inhibited A{beta}-TMEM97 interaction in the APP/PS1+Tau mouse model of AD by treating with the Sigma-2 receptor complex allosteric antagonist CT1812 (n=20) or vehicle (n=20). CT1812 drug concentration correlated negatively with synaptic FRET signal between TMEM97 and A{beta}. These data support a role for TMEM97 in the synaptic binding of A{beta} in human Alzheimer's disease brain where it may mediate synaptotoxicity.

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