Project Title: Interplay of genetic and non-genetic factors in Alzheimer’s disease. Functional response of the aged brain to disease-associated genes
Funding: 120.000,00 €
Funding Agency: Ministerio de Ciencia e Innovación
Summary: Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder characterized by progressive synapse and memory loss. The onset of AD-associated symptoms is preceded by a long time period where the underlying pathogenic mechanisms are thought to initiate. After their debut, AD-associated symptoms continue to progress and culminate in the main clinical hallmarks of AD in later stages of the disease. AD entails an important socio-economic burden due to its high prevalence, the increase in life expectancy of current societies and the lack of an efficient treatment. Despite the efforts and funding attracted into the field, the mechanisms responsible for the age-dependent onset of memory loss and degeneration of synapses and neurons in AD are still incomplete. Understanding the role that the aging brain plays in the onset of AD-associated symptoms is fundamental to develop therapeutic approaches that can stop or alleviate the progression of the disease in patients. We will test the hypothesis that the aged brain has a differential susceptibility and associated molecular mechanisms to the neurodegeneration process that can contribute to the onset of symptoms during aging. For that, we will initiate the pathological process mediated by AD-associated genes at different time points during brain aging using a new AD-related mouse model with spatio-temporal control, and study the neurodegeneration process by functional, behavioral and molecular analysis.
PI: F. Manuel Gómez ; Co-PI: María A. Martínez
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Project Title: Synaptic organizers as hits for memory and synaptic dysfunction in Alzheimer’s disease
Funding: 140.869,56 €
Funding Agency: Junta de Andalucía
Summary: Normal cognitive function requires the correct integration of neurons into highly organized neuronal networks through synaptic contacts. Clinical, genetic and experimental data suggest that impairment in synaptic function is a common finding associated with a wide spectrum of mental disorders where symptoms onset ranges from infancy and early adulthood, as in neurodevelopmental disorders, to late life, as in dementia. Synapse loss correlates with cognitive impairment in neurodegenerative diseases, such as Alzheimer’s disease (AD). However, the pathological pathway that mediates synaptic dysfunction associated with the onset and progression of symptoms in AD is largely unknown. Recent data suggest that synaptic adhesion proteins with the capacity to organize large functional complexes at the synapse might work as disease targets explaining synapse and memory dysfunction in AD. In our group, we study synaptic adhesion complexes that organize the formation, maintenance and function of synaptic networks and their involvement in brain disorders. To this aim, we translate genetic and clinical findings identified in AD to the generation of patient-based mouse models. The functional validation of AD-associated mouse models that recapitulate findings found in patients represents a fundamental tool to identify pathological mechanisms responsible for the onset and progression of the disease, leading to therapeutic targets with clinical value. In this proposal, we aim to study the implication of synaptic organizer systems as a disease mechanism that leads to the onset and progression of symptoms in AD.
PI: F. Manuel Gómez ; Co-PI: María A. Martínez
Other Personnel Assigned to the Project: Claudia Isabel Jove Cifras
