Understanding the genes and pathways that cause Alzheimer’s disease
Affecting over 50 million people worldwide, Alzheimer’s disease (AD) is the most common cause of dementia. And with a new case being diagnosed every 3 seconds, it is also a fast-growing epidemic. In fact, according to some estimates, the number of AD cases is expected to triple within the next 30 years. Despite nearly a century of trying to develop new therapies to treat the disease, so far, all clinical trials have failed. “This highlights the need to identify the molecular mechanisms that drive the disease from its earliest stages, where the potential for intervention and modification is the highest,” says Patricia Rodriguez(opens in new window), an assistant professor at the Karolinska Institute(opens in new window) in Sweden. With the support of the EU-funded NEVULA project, Rodriguez aims to do exactly that. “By better understanding the genes and pathways that can cause AD, we hope to increase our ability to diagnosis the disease early and contribute to the development of new therapeutic interventions for treating it,” she adds.
Filling a knowledge gap
As Rodriguez explains, one of the key pathological hallmarks of AD is the formation of neurofibrillary tangles (NFTs), which are aggregates of the tau protein found in the brain. The NEVULA project focused on a specific layer of neurons that develop NFTs at the earliest stages of AD and that are found in the brain’s entorhinal cortex layer II (ECII) neurons. ECII neurons were of particular interest to researchers because they are the first ones to degenerate in AD. “Surprisingly, we know very little about why these specific cells are particularly vulnerable to degeneration,” explains Rodriguez. According to Rodriguez, this knowledge gap has been one of the biggest challenges in the study – and treatment – of AD. “Our goal was to understand the mechanisms that lead to the early appearance of NFTs and the degeneration of ECII neurons,” she remarks. To do this, researchers used a systems biology approach. By integrating human functional genomics data into the biology of ECII neurons, this approach allows specific disease-associated genes to be highlighted. Based on this process, the project identified four functional modules responsible for NFT formation in AD. “We selected different gene candidates from these modules and manipulated their levels, both in vivo and in vitro, to determine their role in EC neuron function and whether they lead to AD-associated pathological alterations,” says Rodriguez.
Opening the door to additional research
One of the identified genes is a proto-oncogene with a previously unknown function in neurons. Project researchers discovered that this gene regulates neuronal plasticity and excitability, and whose deficiency leads to tau accumulation in ECII neurons. “Our work has demonstrated that our system-level approach is a useful tool for accurately predicting AD-associated genes and pathways,” concludes Rodriguez. “It’s also opened the door to additional research that, ultimately, could lead to a cure for this debilitating disease.” Rodriguez plans to continue her research on the mechanisms that lead to the early degeneration of ECII neurons in AD. Leaning on the many connections she made during her Marie Skłodowska-Curie fellowship(opens in new window), she plans to specifically focus her work on where different genetic and non-genetic risk factors converge to trigger ECII’s vulnerability.
