In a mouse study that focused on synapses, a team of researchers from the University of Edinburgh (UK) revealed how amyloid-β and tau proteins might work together to disrupt cell communication in the brains of individuals with Alzheimer’s disease (AD).
“We were intrigued by the clear neuro-immune signal in our mice with plaques which was only associated with a behavioral phenotype and synaptic gene transcription reductions when tau was present,” commented lead author, Tara Spires-Jones (University of Edinburgh). “This implies that amyloid pathology creates an inflammatory milieu in the brain which is particularly toxic to synapses when tau is present.”
The team observed how the proteins team up to change the expression of genes that are essential for brain signaling, which alters its normal function. When both amyloid and tau proteins were present in the brains of the mouse models, the genes that control synaptic function were less active.
In contrast, some genes that control the immune system were found to be more active, which adds to recent research that suggests that immune cells consume synapses during AD.
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“In support of the translational relevance of this mouse study, in a related paper in press, we observe similar increases in proteins involved in neuron–glia signaling and decreases in proteins important for synaptic function in synaptoneurosomes from [the] human AD brain,” Spires-Jones added.
However, the researchers discovered that these changes were completely reversed when genetic tools were used to reduce the presence of tau. Further, the team reported that being able to reverse the damage caused by the two proteins could help prevent or reverse dementia symptoms.
At present, there is no cure for AD – which currently affects approximately 850,000 individuals and this figure is predicted to rise to more than 1 million by 2025 – however, the findings from this study provide a basis for new potential therapeutic targets.
“In future, we plan to follow up this work further in mice, [the] human brain, and in human cells in culture to try and drill into pathways that may prevent or reverse synapse damage,” concluded Spires-Jones.
Sources: Pickett EK, Hermann AG, McQueen J et al. Amyloid beta and tau cooperate to cause reversible behavioural and transcriptional deficits in a model of Alzheimer’s disease. Cell Rep. doi:10.1016/j.celrep.2019.11.044 (2019) (Epub ahead of print); www.eurekalert.org/pub_releases/2019-12/uoe-dsr120519.php