During the entire ERC consolidator award period, we have achieved our objectives in the Description of Action and have made major advances in our understanding of synapse degeneration in Alzheimer’s disease. Objective 1 was to determine whether the amyloid cascade begins in synapses by examining with pioneering high-resolution imaging whether amyloid beta and tau accumulate together in human synapses and to determine which forms of these proteins accumulate within synaptic terminals. We discovered that amyloid and tau both accumulate in synapses in human Alzheimer’s disease brain, but that they are very rarely within the same synapses (Pickett et al 2019 Cell Reports; Jackson et al 2019 brain Communications; Wang et al 2017 The Journal of Neuroscience; King et al 2022 MedRxiv preprint; Colom-Cadena et al 2021 BioRxiv preprint). In terms of which forms accumulate, we have observed oligomeric amyloid beta within both excitatory and inhibitory synapses and oligomeric, phosphorylated, and misfolded tau within synapses (Jackson et al 2019, Pickett et al 2019, Kurucu et al 2021 European J Neurology, Colom-Cadena et al 2022 in preparation).
Objective 2 was to investigate whether intervening in the cascade from Abeta to tau at synapses allows recovery of synaptic structure and function in a novel mouse model of early Alzheimer’s disease. We indeed observed that lowering tau levels was protective against behavioural deficits in our mouse model, and surprisingly discovered that this appears to be mediated by neuron glia interactions (Pickett et al 2019 Cell Reports). We further proposed to use the drug CT1812 in collaboration with a pharmaceutical company to determine whether stopping Abeta binding to sigma-2 receptors would prevent downstream changes. In this study, we found that treating our mouse model with CT1812 did reduce the interactions of Abeta with the sigma-2 receptor. Futher in human tissue, we discovered that the sigma-2 receptor (TMEM97 protein) does interact with amyloid beta oligomers (Colom-Cadena et al 2021 BioRxiv preprint). These data led to follow on studies with the company which are in progress and will be included in the publication sent for peer review in the coming months. We took our interesting observation of neuron-glia interactions being important in the amyloid cascade back to humans and have observed both microglia and astrocytes ingest tau in human brain, and that cultured human microgila and astrocytes both phagocytose human Alzheimer’s disease synapses more and faster than those from control subjects (Tzioras et al 2019 BioRxiv and updated 2022 version in review).
Objective 3 was to understand pathological mechanisms at synapses and to develop a new stem cell derived neuronal model for these investigations. We published a set of unique induced pluripotent stem cell lines (Toombs et al 2020) and have now used these to model synaptic effects of amyloid beta and tau. In collaboration with a biotech company, we observed that reducing voltage gated potassium channels Kv3.4 in a mouse model of Alzheimer’s ameliorated synapse loss and that challenging iPSC neurons with human Alzheimer’s brain homogenate caused a rapid decrease on Kv3.4 expression, perhaps as a compensatory mechanism for synaptotoxicity (Yeap et al 2022 Brain and Neuroscience Advances). We further observe that synaptic protein expression is changed in iPSC derived neurons in response to this human AD brain challenge (King et al 2022 MedRxiv). The final data analyses from the final 2 objectives ( 3b and 3c) using these neurons are in the final stages and I will finish the papers in the coming months. We discovered novel mechanisms of synapse degeneration using several approaches throughout the project including the involvement of mitochondria in synapse degeneration (Pickett et al 2018 Acta Neuropath), collaborative work showing tau binding synaptogyrin 3 in synapses (Zhou et al 2017 Nature communications, McInnes et al 2018 Neuron, Largo-Barrientos et al 2021 Neuron)
Altogether, the ALZSYN project revealed complex interactions between amyloid beta and tau in synapse degeneration and revealed a role for microglia and astrocytes in the amyloid cascade. These results have led to over a dozen primary research papers on which I am first author, over a dozen papers on which we contributed related data as collaborators, and over a dozen invited editorials, reviews and commentaries in high profile journals including Science, Nature Reviews Neuroscience and Nature Neuroscience. In addition, this award was instrumental in leveraging over 2 million euros in further funding from national funding bodies, charities, and pharmaceutical companies. Further, our collaborative work including ALZSYN data have been instrumental in contributing to clinical trials of a drug (Izzo et al 2021Alzheimer’s and Dementia).
