Presenilin Is the Molecular Target of Acidic γ-Secretase Modulators in Living Cells

The intramembrane-cleaving protease γ-secretase catalyzes the last step in the generation of toxic amyloid-β (Aβ) peptides and is a principal therapeutic target in Alzheimer's disease. Both preclinical and clinical studies have demonstrated that inhibition of γ-secretase is associated with prohibitive side effects due to suppression of Notch processing and signaling. Potentially safer are γ-secretase modulators (GSMs), which are small molecules that selectively lower generation of the highly amyloidogenic Aβ42 peptides but spare Notch processing. GSMs with nanomolar potency and favorable pharmacological properties have been described, but the molecular mechanism of GSMs remains uncertain and both the substrate amyloid precursor protein (APP) and subunits of the γ-secretase complex have been proposed as the molecular target of GSMs. We have generated a potent photo-probe based on an acidic GSM that lowers Aβ42 generation with an IC50 of 290 nM in cellular assays. By combining in vivo photo-crosslinking with affinity purification, we demonstrated that this probe binds the N-terminal fragment of presenilin (PSEN), the catalytic subunit of the γ-secretase complex, in living cells. Labeling was not observed for APP or any of the other γ-secretase subunits. Binding was readily competed by structurally divergent acidic and non-acidic GSMs suggesting a shared mode of action. These findings indicate that potent acidic GSMs target presenilin to modulate the enzymatic activity of the γ-secretase complex

WHEDA study: Effectiveness of occupational therapy at home for older people with dementia and their caregivers - the design of a pragmatic randomised controlled trial evaluating a Dutch programme in seven German centres

Contains fulltext : 80941.pdf (publisher's version ) (Open Access)BACKGROUND: A recent Dutch mono-centre randomised controlled trial has shown that occupational therapy improves daily functioning in dementia. The aim of this present study is to compare the effects of the Dutch community occupational therapy programme with a community occupational therapy consultation on daily functioning in older people with mild or moderate dementia and their primary caregivers in a German multi-centre context. METHODS/DESIGN: A multi-centre single blind randomised controlled trial design is being used in seven health care centres (neurological, psychiatric and for older people) in urban regions. Patients are 1:1 randomised to treatment or control group. Assessors are blind to group assignment and perform measurements on both groups at baseline, directly after intervention at 6 weeks and at 16, 26 and 52 weeks follow-up. A sample of 140 community dwelling older people (aged >65 years) with mild or moderate dementia and their primary caregivers is planned. The experimental intervention consists of an evidence-based community occupational therapy programme including 10 sessions occupational therapy at home. The control intervention consists of one community occupational therapy consultation based on information material of the Alzheimer Society. Providers of both interventions are occupational therapists experienced in treatment of cognitively impaired older people and trained in both programmes. 'Community' indicates that occupational therapy intervention occurs in the person's own home. The primary outcome is patients' daily functioning assessed with the performance scale of the Interview for Deterioration in Daily Living Activities in Dementia and video tapes of daily activities rated by external raters blind to group assignment using the Perceive, Recall, Plan and Perform System of Task Analysis. Secondary outcomes are patients' and caregivers' quality of life, mood and satisfaction with treatment; the caregiver's sense of competence, caregiver's diary (medication, resource utilisation, time of informal care); and the incidence of long-term institutionalisation. Process evaluation is performed by questionnaires and focus group discussion. DISCUSSION: The transfer from the Dutch mono-centre design to the pragmatic multi-site trial in a German context implicates several changes in design issues including differences in recruitment time, training of interventionists and active control group treatment.The study is registered under DRKS00000053 at the German register of clinical trials, which is connected to the International Clinical Trials Registry Platform

Characterization of a Drosophila Alzheimer's Disease Model: Pharmacological Rescue of Cognitive Defects

Transgenic models of Alzheimer's disease (AD) have made significant contributions to our understanding of AD pathogenesis, and are useful tools in the development of potential therapeutics. The fruit fly, Drosophila melanogaster, provides a genetically tractable, powerful system to study the biochemical, genetic, environmental, and behavioral aspects of complex human diseases, including AD. In an effort to model AD, we over-expressed human APP and BACE genes in the Drosophila central nervous system. Biochemical, neuroanatomical, and behavioral analyses indicate that these flies exhibit aspects of clinical AD neuropathology and symptomology. These include the generation of Aβ40 and Aβ42, the presence of amyloid aggregates, dramatic neuroanatomical changes, defects in motor reflex behavior, and defects in memory. In addition, these flies exhibit external morphological abnormalities. Treatment with a γ-secretase inhibitor suppressed these phenotypes. Further, all of these phenotypes are present within the first few days of adult fly life. Taken together these data demonstrate that this transgenic AD model can serve as a powerful tool for the identification of AD therapeutic interventions

Neuropsychiatric symptoms in Alzheimer\u27s disease: Past progress and anticipation of the future

Neuropsychiatric symptoms (NPS) in Alzheimer\u27s disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimer\u27s first case, Frau Auguste D., presented with emotional distress and delusions of infidelity/excessive jealousy, followed by cognitive symptoms. Being cognizant of this, in 2010 the Alzheimer\u27s Association convened a research roundtable on the topic of NPS in AD. A major outcome of the roundtable was the founding of a Professional Interest Area (PIA) within the International Society to Advance Alzheimer\u27s Research and Treatment (ISTAART). The NPS-PIA has prepared a series of documents that are intended to summarize the literature and provide more detailed specific recommendations for NPS research. This overview paper is the first of these living documents that will be updated periodically as the science advances. The overview is followed by syndrome-specific synthetic reviews and recommendations prepared by NPS-PIA workgroups on depression, apathy, sleep, agitation, and psychosis. © 2013 The Alzheimer¢s Association. All rights reserved