Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease

Synapse loss correlates with cognitive decline in Alzheimer’s disease, and soluble oligomeric amyloid beta is implicated in synaptic dysfunction and loss. An important knowledge gap is the lack of understanding of how amyloid beta leads to synapse degeneration. In particular, there has been difficulty in determining whether there is a synaptic receptor that binds amyloid beta and mediates toxicity. While many candidates 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 amyloid beta binding at individual synapses. To overcome this limitation, we combined two high resolution microscopy techniques: array tomography and Förster 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, amyloid beta generates a FRET signal with transmembrane protein 97, cellular prion protein, and postsynaptic density 95. Transmembrane protein 97 is also present in a higher proportion of postsynapses in Alzheimer’s brain compared to controls. Further, we inhibited amyloid beta / transmembrane protein 97 interaction in a mouse model of amyloidopathy by treating with the an allosteric modulator CT1812 or vehicle. CT1812 drug concentration correlated negatively with synaptic FRET signal between transmembrane protein 97 and amyloid beta. In human induced pluripotent stem cell derived neurons challenged with human Alzheimer’s brain homogenate, transmembrane protein 97 and amyloid beta are present in synapses. Transcriptional changes are induced by Aβ including changes in genes involved in neurodegeneration and neuroinflammation. CT1812 treatment of these neurons caused changes in gene sets involved in synaptic function. These data support a role for transmembrane protein 97 in the synaptic binding of amyloid beta in human Alzheimer’s disease brain where it may mediate synaptotoxicity. ### Competing Interest Statement TSJ is a member of the scientific Advisory Board of Cognition Therapeutics. LW, AOC, MH, NI and SC are or were employees of Cognition Therapeutics. * Aβ : amyloid beta TMEM97 : transmembrane protein 97 PSD95 : postsynaptic density 95 PrPc : cellular prion protein PGRMC1 : Progesterone receptor membrane component 1.