Periodic Reporting for period 2 - DIVE into AD (Study of tau strains to understand the phenotypic diversity of Alzheimer’s disease: A step toward personalized therapies)
Periodo di rendicontazione: 2021-08-01 al 2022-07-31
Alzheimer’s disease (AD) is the most prevalent form of dementia and the most frequently occurring neurodegenerative disorder. While the life expectancy is continuously increasing in most countries, the number of AD cases is expected to increase massively in the near future. Understanding the underlying mechanisms of disease must be a priority in order to design effective therapies that are able to slow down or cure this debilitating disorder. AD is a heterogeneous disease that is responsible for a diversity of clinical presentations that include a wide spectrum of rate of cognitive decline or rare focal variants of the disease.The symptoms of AD are closely related to the accumulation in the brain of a protein named tau, that is able to propagate from one brain region to another. Abnormal tau protein can enter recipient neurons and recruit the normal tau inside neuron to build toxic aggregates. This process is called seeding. Differences in tau seeding at the individual level might be responsible for the heterogeneity of clinical presentation.
We believe that the development of sensitive tools to characterize and measure tau seeding activity in biological samples will help not only to understand AD physiopathology but also to design more specific therapies that will benefit the society.
We believe that the development of sensitive tools to characterize and measure tau seeding activity in biological samples will help not only to understand AD physiopathology but also to design more specific therapies that will benefit the society.
Ultra sensitive tools were developed to measure tau seeding activity in biological samples. The molecular signature of tau was studied in a cohort of AD brains and demonstrated heterogeneity from case to case. In this cohort, the bioactivity of tau, was correlated to the clinical rate of cognitive decline in individual patients. Therefore, the novel tools used to detect seeding in bio fluids such as lumbar cerebrospinal fluid (the liquid that circulates around the brain and spinal cord) can bring novel biomarkers potentially with some prognostic value.
Additionally, the exploration of the molecular mechanisms and pathways responsible for tau uptake by neurons revealed that the Low density lipoprotein receptor-related protein 1 (LRP-1) not only contributes to tau internalization and degradation but is also involved in a pathway leading to pathological seeding. SORL1 a protein that is structurally related to LRP-1 was also shown to contribute to tau seeding.
Additionally, the exploration of the molecular mechanisms and pathways responsible for tau uptake by neurons revealed that the Low density lipoprotein receptor-related protein 1 (LRP-1) not only contributes to tau internalization and degradation but is also involved in a pathway leading to pathological seeding. SORL1 a protein that is structurally related to LRP-1 was also shown to contribute to tau seeding.
The characterization of the molecular determinants of AD heterogeneity with the demonstration of the existence of different tau stains with varying seeding competency will have a significant impact. In the current era of immunotherapies in neurodegenerative disorders, this can modify remarkably the way clinical trials are designed and their results analyzed. It may open the way to personalized medicine strategies for patients with particular tau characteristics. Finally it may help understanding the variability in disease progression and potentially may help predicting the fate of individual patients. Taken together, the results of this program may decrease the global burden of AD on our aging societies.