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Presenile dementia

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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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A Look Inside Alzheimer's is a captivating read for friends, families and loved ones affected by this mind-robbing disease. Individuals with early-stage Alzheimer's disease will take comfort in the voice of a fellow traveler experiencing similar challenges, frustrations, and triumphs. Family and professional caregivers will be enlightened by this book and gain a better understanding of this unfathomable world and how best to care for someone living in it. Susan and PJ, share their accounts of their own transformation and deterioration with early-onset Alzheimer's Disease and Marjorie shares he

Alzheimer's disease. --- Presenile dementia. --- Pick's disease of the brain --- Dementia --- Alzheimer disease --- Alzheimer's dementia --- Basal ganglia --- Presenile dementia --- Senile dementia --- Diseases

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Advances in Alzheimer's disease (AD) research have been challenging and without major breakthroughs in understanding its pathological basis. The reigning hypothesis suggests AD is the result of extracellular amyloid deposition that seed to form amyloid plaques, which then grow and kill neighboring neurons. However, there are several inconsistencies with this hypothesis, not to mention the inability to show clinical benefit in several failed clinical trials by pharmaceuticals (i.e., from Pfizer, Eli Lilly, etc.), and it is in the field's best interest to explore and test multiple hypotheses fo

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

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Clive Beaumont was diagnosed with Younger Onset Dementia at age 45, when his children were aged just 3 and 4. Clive's wife, Helen, tells of how she and the rest of the family made it through the next six years until Clive died: the challenge of continually adapting to his progressive deterioration.

Presenile dementia --- Pick's disease of the brain --- Dementia --- Patients --- Beaumont, Clive --- Mental health.