Adult Hippocampal Neurogenesis

: A potential converging mechanism for Major Depressive Disorder and Alzheimer’s Disease

Abstract

Mental health disorders are widespread throughout society. Two of the most common diseases are dementia and depression. About 50 million people suffer from dementia (70 % Alzheimer’s Disease, AD) and around 6 % of the worldwide population from Major Depressive Disorder (MDD) worldwide. Clinical studies report correlations between AD and MDD. AD patients are more likely to develop depressive symptoms and impaired cognition is a common symptom of both disorders. One brain region where the production of new neurons continues throughout life is the hippocampus. The generation and integration of new neurons is crucial for cognition and mood regulation. Previous studies suggested that hippocampal neurogenesis is altered in MDD and AD, however, no cellular mechanism has been proposed to connect them. Therefore, I investigated the role of hippocampal neurogenesis in MDD and AD and its potential role as a common risk mechanism. Using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), isogenic induced pluripotent stem cell (iPSC) lines were generated harbouring mutations that are likely to affect neurogenesis based on significance levels in genome-wide association studies (GWAS) and bioinformatic predictions. These cell lines were differentiated into hippocampal granule neuron-like cells to investigate the effect of these mutations. For AD, an intronic single- nucleotide polymorphism (SNP) in the gene Protein Tyrosine Kinase 2 Beta (PTK2B) was selected (rs28834970). For MDD, an intronic SNP in the Leucine-rich repeat and fibronectin type- III domain-containing protein 5 (LRFN5) gene was investigated (rs1950829). Both risk variants and knockouts of respective genes affected neurogenesis-related processes, including granule neuron specification, differentiation efficiency, neurite outgrowth, survival, synapse formation, activity, and excitability. Moreover, gene expression data of MDD cell lines indicated dysregulation of AD-associated genes and a possible link to PTK2B, connecting both diseases. Taken together, the data generated here strengthens the idea that dysregulated hippocampal neurogenesis could be a converging risk mechanism for MDD and AD.

Date of Award	1 Sept 2022
Original language	English
Awarding Institution	King's College London
Supervisor	Sandrine Thuret (Supervisor), Dag Aarsland (Supervisor) & Timothy Powell (Supervisor)