Tau-proximity ligation assay reveals extensive previously undetected pathology prior to neurofibrillary tangles in preclinical Alzheimer’s disease

Journal article

In Alzheimer's disease, fibrillar tau pathology accumulates and spreads through the brain and synapses are lost. Evidence from mouse models indicates that tau spreads trans-synaptically from pre- to postsynapses and that oligomeric tau is synaptotoxic, but data on synaptic tau in human brain are scarce. Here we used sub-diffraction-limit microscopy to study synaptic tau accumulation in postmortem temporal and occipital cortices of human Alzheimer's and control donors. Oligomeric tau is present in pre- and postsynaptic terminals, even in areas without abundant fibrillar tau deposition. Furthermore, there is a higher proportion of oligomeric tau compared with phosphorylated or misfolded tau found at synaptic terminals. These data suggest that accumulation of oligomeric tau in synapses is an early event in pathogenesis and that tau pathology may progress through the brain via trans-synaptic spread in human disease. Thus, specifically reducing oligomeric tau at synapses may be a promising therapeutic strategy for Alzheimer's disease.We gratefully acknowledge the contributions of our brain tissue donors and their families, the Edinburgh Brain and Tissue Bank and Alzheimer’s Scotland Dementia Research Centre for coordinating brain tissue donations, Edinburgh Neuroscience for facilitating collaborations, and Prof. Rakez Kayed for generously providing T22 antibody. This work was supported by the Medical Research Council Centres of Excellence in Neurodegeneration (CoEN5025), Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 681181), and the UK Dementia Research Institute, which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society, and Alzheimer’s Research UK. The confocal microscope was generously funded by Alzheimer’s Research UK and a Wellcome Trust Institutional Strategic Support Fund at the University of Edinburgh. J.L. was funded by UCB Biopharma, as was the Oxford Nanoimager. M.H. and J.L. acknowledge funding from Dr. Jim Love.Peer reviewe

Authors: Bengoa-Vergniory, N; Velentza-Almpani, E; Silva, AM; Scott, C; Vargas-Caballero, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: BioMed Central
• Journal: Acta Neuropathologica Communications
• Volume: 9
• Issue: 1
• Pages: 18-18
• Article number: 18
• Publication date: 2021-01-28
• DOI: 10.1186/s40478-020-01117-y
• EISSN: 2051-5960
• ISSN: 2051-5960
• Language: English
• Keywords: Medicine; Biology; Neurology; Pathology; Alzheimer's disease; Neuroscience; Neurofibrillary tangle; Tau pathology; Senile plaques; Disease