Molecular Horizons PhD Exit Seminar - Rachelle Balez

Sporadic Alzheimer’s disease (sAD) is the most common form of dementia, causing progressive memory loss for patients, yet there are limited treatments and no cure. Within the brain, neuronal calcium signalling is postulated to underly the encoding of memories, however it is disrupted during sAD. Increased nitrosative and oxidative stress is common during sAD and can drive alterations in the lipid membrane, which could contribute to changes in neuronal calcium signalling.

This thesis utilised induced pluripotent stem cell-derived neurons generated from sAD patients to investigate the impact of nitrosative stress and alterations to the lipid membrane on neuronal calcium signalling, and the neuroprotective capacity of the lipid soluble antioxidant, α-tocopherol, against these pathogenic changes.

The work from this thesis shows that sAD neurons have an increased expression of neuronal nitric oxide synthase (nNOS), a calcium activated enzyme capable of producing reactive nitrogen and oxygen species, in addition to decreased endogenous resilience and increased susceptibility to ferroptosis. Further, these changes contributed to a complex dysfunctional calcium signalling phenotype in sAD neurons. Supplementation with α-toc or modulation of nNOS activity was able to mediate aspects of aberrant calcium signalling, reduce markers of nitrosative stress and minimise ferroptosis induced membrane alterations.

These findings demonstrate that nitrosative and oxidative stress, as well as lipid membrane alterations, contribute to the disruption of neuronal calcium signalling during sAD.