RT Journal Article
SR Electronic
T1 TMEM97 increases in synapses and is a potential synaptic Aβ binding partner in human Alzheimer’s disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.02.01.428238
DO 10.1101/2021.02.01.428238
A1 Martí Colom-Cadena
A1 Jane Tulloch
A1 Rosemary J Jackson
A1 James H Catterson
A1 Jamie Rose
A1 Caitlin Davies
A1 Monique Hooley
A1 Alejandro Anton-Fernandez
A1 Sophie Dunnett
A1 Robert Tempelaar
A1 Makis Tzioras
A1 Nicholas J Izzo
A1 Susan M. Catalano
A1 Colin Smith
A1 Tara L. Spires-Jones
YR 2021
UL http://biorxiv.org/content/early/2021/02/01/2021.02.01.428238.abstract
AB Synapse loss correlates with cognitive decline in Alzheimer’s disease (AD), and soluble amyloid beta (Aβ) is implicated in synaptic dysfunction and loss. An important knowledge gap is the lack of understanding of how synaptic accumulation of Aβ leads to synapse degeneration. In particular, there has been difficulty in determining whether there is a synaptic receptor that binds Aβ 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 Aβ 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, Aβ 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 Aβ-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 Aβ. These data support a role for TMEM97 in the synaptic binding of Aβ in human Alzheimer’s disease brain where it may mediate synaptotoxicity.One Sentence Summary In Alzheimer’s disease, TMEM97 was present in a higher proportion of synapses and close enough to amyloid beta to be a potential synaptic binding partner.Competing Interest StatementTSJ is a member of the scientific Advisory Board of Cognition Therapeutics. NI and SC are employees of Cognition Therapeutics.