Seminar – Lucas GEPHINE

Cognitive Resilience in Alzheimer’s Disease: The LOU/C/Jall Rat Model

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder that progressively leads to severe cognitive decline, executive dysfunction, and loss of autonomy. Despite the hope raised by new monoclonal therapies targeting amyloid protein, AD remains incurable to date, particularly due to marked interindividual heterogeneity. Although similar neuropathological markers may be present, some older individuals preserve intact cognitive function compared to others.

To explain this lack of correlation between the extent of brain lesions and the severity of cognitive symptoms, the concept of cognitive resilience (CR) has emerged. This dynamic process has been proposed to account for both variability in response to AD pathology and therapeutic failure. Although several preclinical and clinical studies have identified potential neurobiological mechanisms underlying CR, further research is needed, as these mechanisms remain poorly understood.

The aim of Lucas Gephine’s thesis was to investigate the brain mechanisms potentially involved in cognitive resilience. The experimental design combined a preclinical model of successful aging (LOU/C/Jall rat: LOU) and a standard strain (Wistar rat: WIS), with two sporadic models of AD: intrahippocampal injection of AAV-APP/PS1 viral vectors and intracerebroventricular injection of streptozotocin (STZ).

The AAV-APP/PS1 model did not allow the identification of CR in LOU rats, due to the absence of induced cognitive deficits and AD-related neuropathological markers in WIS rats. In contrast, the STZ model revealed cognitive resilience in LOU rats, characterized by preserved cognitive performance in two behavioral tasks assessing spatial working memory and object recognition memory, despite similar hippocampal and cortical Aβ42 concentrations.

Proteomic analysis revealed differential regulation of several proteins in LOU-STZ rats. These proteins were involved in pathways related to DNA repair, mitochondrial and ribosomal stability and integrity, immune response, and tau protein stabilization.

Overall, this work highlights the importance of investigating the neurobiological mechanisms underlying cognitive resilience in order to identify novel biomarkers that may guide therapeutic research in the context of Alzheimer’s disease.