Role of reactive microglia and intraneuronal amyloids on neuronal vulnerability in early Alzheimer’s disease

The recently approved drugs for Alzheimers disease (AD), targeting amyloid plaques removal, only mildly slow patients cognitive decline as neuronal loss starts decades before plaque deposition. To delay AD onset before symptoms development, prevention of neuronal death should be prioritised instead.

An early AD pathological event is intraneuronal accumulation of amyloids (intraA) which can cause neuronal death at the pre-plaque stage.

IntraA is only found in specific neuronal subtypes first to be lost in AD, suggesting it might underly their selective vulnerability.

Reactive microglia could contribute to intraA as blocking neuroinflammatory processes in early AD reduces its accumulation.

Whether microglia also contribute to intraA+ neurons selective loss is still unknown but could suggest repurposing of already available microglia targeting drugs for early neuroprotective therapies.

I will test this hypothesis in 5xFAD mice, first confirming intraA accumulates in the neuronal subtypes selectively lost, as it occurs in humans.

I will analyse the contribution of reactive microglia to intraA neurons death by pharmaceutically rescuing their reactivity and determine if intraA neurons-associated microglia express AD high-risk genes, which drive late AD pathology.

Because AD affects women more, possibly due to their higher inflammatory response, the sex-specificity in the previous analyses will also be tested.

Finally, I will establish microglia-containing human brain organoids to recapitulate this synergy in a in vitro human AD model, providing a foundation for future drug testing.By determining the potentially detrimental interplay between microglia reactivity and intraA+ neurons, using both in vivo and in vitro models, my project will lay the basis of extensive future work while defining my research niche.

In the long term, my results will impact development of novel neuroprotective therapies for treating AD before neuronal loss.