Inhibitory synapse loss and accumulation of amyloid beta in inhibitory presynaptic terminals in Alzheimer’s disease - Kurucu et al

# Background # Synapse degeneration in Alzheimer’s disease (AD) correlates strongly with cognitive decline. There is well-established excitatory synapse loss in Alzheimer’s disease with known contributions of pathological amyloid beta (Ab) to excitatory synapse dysfunction and loss. Despite clear changes in circuit excitability in AD and model systems, relatively little is known about pathology in inhibitory synapses.
# Methods #
Here we examined human post-mortem brain samples (n=5 control, 10 AD cases) from temporal and occipital cortices to examine whether inhibitory synapses and neurons are lost in AD and whether Ab may contribute to inhibitory synapse degeneration. Inhibitory neurons were counted in all 6 cortical layers using stereology software, and array tomography was used to examine synapse density and accumulation of Ab in synaptic terminals.
# Results #
We observe differing inhibitory neuron densities in the different cortical layers and brain regions with significantly lower inhibitory neuron density in AD than in control cases. High-resolution array tomography imaging reveals plaque-associated loss of inhibitory synapses and accumulation of Ab in a small subset of inhibitory pre-synaptic terminals with the most accumulation near amyloid plaques.
# Conclusions #
Inhibitory neuron and synapse loss in AD may contribute to disrupted excitatory/inhibitory balance and cognitive decline. Future work is warranted to determine whether targeting inhibitory synapse loss could be a useful therapeutic strategy.
# Acknowledgments #
This study was funded by a European Academy of Neurology Fellowship, the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement No. 681181), Wellcome Trust PhD studentships, and the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council. Several of our control participants were recruited through the Lothian Birth Cohort 1936 study in the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology which were supported by Age UK (Disconnected Mind Project), BBSRC, and MRC (MR/K026992/1).

Spires-Jones, Tara L. (2021). Inhibitory synapse loss and accumulation of amyloid beta in inhibitory presynaptic terminals in Alzheimer’s disease - Kurucu et al, [dataset]. University of Edinburgh. https://doi.org/10.7488/ds/3098.