Luciano D'Adamio - US grants

DESCRIPTION (provided by applicant): The familial Alzheimer's disease gene product amyloid Beta (ABeta) precursor protein (APP) is processed to generate ABeta which is considered to be one of the major culprits of Alzheimer's disease. APP is first processed extracellularly by the alpha- or Beta-secretase creating either a C83 or C99 membrane tether fragment, respectively, and then by the gamma-secretase in the transmembrane domain. Processing by the Beta- and gamma-secretase leads to production of ABeta as well as AID (APP Intracellular Domain) which is derived from APP's extreme carboxy terminus. AID was originally shown to lower the cellular threshold to apoptosis and more recently has been shown to modulate gene expression and cellular calcium homeostasis. APP is a member of a gene family that includes the APP like molecules APLP1 and APLP2. Studies using knock out mice have demonstrated that APP, APLP1 and APLP2 have partially redundant functions as well as unique roles. Since APP signals by releasing the biologically active AID peptide, it is possible that APLP1 and APLP2 also release biologically active APP Like Intracellular Domains ALIDs due to processing by the g-secretase. The major goals of the current proposal are to characterize the signaling pathways regulated by APP, APLP1 and APLP2 processing. These studies could unveil the signaling pathways that are either common or specific and unique to each APP family member. In this context, we will also study the trafficking of APP family members in primary neurons. The transport of APP in neurons may be of great relevance to the biological function of APP in neuronal ceils and may regulate neurite growth. These studies may clarify the biological role of APP family members and have important practical applications in the development of new compounds for the cure and or prevention of Alzheimer's disease.

DESCRIPTION (provided by applicant): The Familial Alzheimer's disease gene product Amyloid beta Precursor Protein (APP) undergoes extensive processing. APP cleavage by secretases has been studied in great detail because it generates Abeta peptides that are implicated in the pathogenesis of Alzheimer's disease. Recent data indicate that the intracellular domain of APP (AID), released together with Abeta, has signaling functions. AID can induce cell death, plays a role in the regulation of gene transcription and regulates calcium release from endoplasmic reticulum stores. We have found that AID can repress Notch-dependent transcription and that this restraint may be mediated by the interaction of AID with the Notch inhibitors Numb/Numblike (Nbl). Numb has also been involved in receptors endocytosis and endocytosis of APP is known to regulate APP processing. Based on these findings, we hypothesize that Numb/Nbl proteins mediate the inhibitory effect of AID on Notch signaling and regulate APP endocytosis and processing. In this application, we propose to study the role of Numb/Nbl proteins in inhibition of Notch by AID, in APP endocytosis and APP processing. Aside for their relevance to the biology of APP. these studies may have implications pertinent to the therapy and pathology of Alzheimer's disease. Drugs designed to lower Abeta production might also alter the levels of AID. Therefore a clear understanding of the biological functions of AID may help in predicting and preventing toxic effects due to alterations in AID production by these inhibitors. Furthermore, inhibition of Notch signaling by AID might accelerate the neurodegenerative process of Alzheimer's disease by enhancing synapse loss, neurite dystrophy and neuronal degeneration. Lastly, regulation of APP endocytosis and processing by Numb/Nbl proteins might provide potential new targets for compounds aimed to reduce Abeta production.

[unreadable] DESCRIPTION (provided by applicant): Alzheimer's disease (AD) pathogenesis is firmly associated with the processing of the transmembrane amyloid precursor protein (APP), as demonstrated by the fact that mutations in APP or in the enzymes responsible for its processing cause Familial Alzheimer's disease. Because of its biological and pathological importance, understanding how APP cleavage is controlled is of great relevance. Based on the analogy between APP and Notch signaling, we have postulated the existence of integral membrane proteins that can bind APP, regulating its processing. We have recently identified as a putative APP ligand BRI2, a protein found mutated in patients with Familial British and Danish Dementia (FBD and FDD), two diseases clinically and pathologically similar to Alzheimer's disease. Our preliminary data show that BRI2 inhibits APP processing and, in turn, Abeta production in cell lines. Moreover, BRI2 mutants, which cause FBD and FDD, are less potent inhibitors of APP processing. These findings suggest that BRI2 regulates and/or modifies AD pathogenesis and that BRI2 FBD and FDD mutants are ineffective inhibitors of Abeta generation in vivo. This last point hints to the possibility that dis-regulation of APP processing may participate in the pathogenesis of FDD and FBD. [unreadable] [unreadable] Here, we propose to generate animal models to test these hypotheses. The development of these animal models would provide unvialable tools for a better understanding the pathogenesis of Alzheimer's disease, and perhaps FDD and FBD, as well as a valuable system for the evaluation of novel therapeutic strategies directed toward these pathogenic processes. [unreadable] [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): This application requests partial support for a meeting on the Neurobiology of Brain Disorders, this time with a special emphasis on the impact of aging on the dysfunction of the nervous system, as part of a Gordon Research Conference series to be held at Melia Golf Vichy Catalan Resort near Girona, Spain from August 7- August 12, 2016. The Specific Aims of this GRC are to bring together leading scientists who are at the forefront of the field of neurodegenerative and aging-related disorders of the nervous system to present and discuss their latest findings and concepts. The Conference will feature wide-ranging, but related topics that are relevant to common disease mechanisms of different neurodegenerative and aging-related disorders, such as synaptic dysfunction, protein homeostasis-misfolding-aggregation, circuit and network dysfunction, genetic factors, RNA mechanisms, therapeutic opportunities and biomarkers. Invited speakers represent a wide variety of scientific disciplines, including genetics, biochemistry, cell biology, electrophysiolog and imaging technology. Every effort will be made to encourage participation of graduate students, postdoctoral fellows and junior faculty members as well as women and underrepresented minorities. The Conference will provide opportunities for junior scientists to present their work in poster sessions and to interact informally with leaders in the field. In addition, short talks will be selected from submitted posters, so junior scientists will have opportunities to participate in oral presentations. The collegial atmosphere and the ample free time in the afternoons and late evenings provide ideal settings for participants from different disciplines to brainstorm and establish interdisciplinary collaborations. The significance of this application is that this GRC will provide a unique forum for the international community working on the neurobiology of brain disorders to come together and discuss the latest advances and the future challenges in the field of neurodegeneration and aging-related disorders of the nervous system. The relevance of this application to public health is that the discussions generated will help define the most pertinent important questions in the field of neurodegenerative diseases in terms of both basic biology and disease mechanisms, which will aid the development of novel therapeutic strategies for these devastating diseases that are major public health problems. The long-term goal of this GRC is to provide a consistent platform for the community to meet regularly (every two years) in order to disseminate the most recent discoveries and to formulate the most important questions concerning the current state of the art research on brain disorders.