N. (Natalia) Orti Casañ

PhD thesis: Neuroinflammation - Friend or foe in Alzheimer's disease? Modulating the immune system as therapeutic strategy (2023)

Alzheimer’s disease (AD) is a devastating neurodegenerative disease and the most common form of dementia that currently affects 55 million people globally. AD is characterized by loss of memory, changes in mood and behavior and the inability to perform daily tasks. Despite decades of exhaustive research, no successful treatment has been discovered for AD.

Besides the characteristic pathology observed in the AD brain, inflammation of the brain (known as neuroinflammation) and the involvement of the immune system have emerged as new therapeutic venues. The main objective of this thesis was to modulate the immune system as strategy to ameliorate cognitive deficits and AD-related neuropathology. To this end, we focused on the signaling of a specific protein, TNF-α, which plays a key role in the orchestration of the immune response. TNF-α can activate two different signaling pathways and exert opposing functions: activation of one pathway leads to inflammation and cell death whereas activation of the second pathway leads to cell survival and neuroprotection.

In this thesis, we discovered that activating the neuroprotective signaling pathway of TNF-α in different AD mouse models results in a significant improvement of cognitive functions as well as a drastic reduction in AD neuropathology. Thus, modulation of TNF-α signaling seems like an effective strategy for the treatment of AD.

This thesis has provided a more in depth understanding on the role, mechanisms and effects of modulating the immune system in AD and proposed new potential therapeutic strategies that can be explored in the future for the treatment of AD.