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γ-Secretase complexes constitute a family of proteases first identified in Alzheimer's disease (AD) patients and involved in multiple signaling pathways. These unusual enzymes are embedded in the membrane where they cut consecutively several substrates, including the amyloid precursor protein (APP). Pathogenic mutations in the catalytic core of γ-secretase (PSEN), as well as, in APP cause early onset familial AD (FAD, <65 y). The fact that AD linked mutations are found both in the enzyme (PSEN/γ-secretase) and substrate (APP) that generate Aβ peptides strongly supports the amyloid cascade hypothesis, which proposes that AD is caused by an imbalance between Aβ peptides production and their clearance.Independently of the position and nature of the mutation in PSEN, all pathogenic substitutions exert a common impairment on γ-secretase processivity, which leads to production of longer, amyloidogenic Aβ peptides. Majority of pathogenic mutations in APP impact the aggregation properties of APP, either directly or indirectly, by affecting the carboxypeptidase like processing of APP resulting in longer Aβ peptides. Despite its relevance, an experimentally verified and internally consistent model explaining the effects of PSEN and APP pathogenic substitutions on γ-secretase function is lacking. Moreover, an increasing amount of data is emerging giving evidence for possible alterations of Aβ production in a subset of sporadic AD patients, further underlying the significance of deciphering the molecular basis of γ-secretase dysfunction.The rational of this PhD project is based on the high conformational plasticity and metastable fold of PSEN. We propose that PSEN structural flexibility resulting from the inefficient structural packing plays key roles in global activity and processivity of γ-secretase. Our goal is to decipher the molecular mechanisms and structural determinants underlying the pathogenic effects mediated by γ-secretase in both familial and sporadic forms of AD.

Presenile dementia --- Alzheimer's disease --- Academic collection

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"Nearly 5.3 million Americans are living with Alzheimer's disease, and 26.6 million people are affected worldwide. The Alzheimer's Disease Neuroimaging Initiative (ADNI), a public-private partnership, provides a publicly available, international database of clinical and imaging data to foster research and collaboration on Alzheimer's research worldwide. The Institute of Medicine held a workshop on July 12, 2010, to explore opportunities to use information from and partnerships formed because of ADNI to continue to improve the understanding and treatment of Alzheimer's disease."--Publisher's description.

Alzheimer's disease --- Alzheimer disease --- Alzheimer's dementia --- Basal ganglia --- Presenile dementia --- Senile dementia --- Imaging. --- Diseases

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Alzheimer's disease --- Pathophysiology. --- Alzheimer disease --- Alzheimer's dementia --- Basal ganglia --- Presenile dementia --- Senile dementia --- Diseases

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The prevalence of dementia is increasing rapidly as the population ages and there is a steady rise in people with dementia being admitted to acute hospitals. Media coverage of the care received by people with dementia in acute hospitals is almost wholly negative. The purpose of this book is to provide a detailed description of what the experience, both positive and negative, is really like from the perspectives of patients, lay carers, and health and social care staff, and to propose a model ...

Alzheimer's disease. --- Alzheimer disease --- Alzheimer's dementia --- Basal ganglia --- Presenile dementia --- Senile dementia --- Diseases

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Alzheimer's disease. --- Alzheimer disease --- Alzheimer's dementia --- Basal ganglia --- Presenile dementia --- Senile dementia --- Diseases