Alzheimer’s disease (AD) is the most common form of dementia, with more than 25 million people worldwide suffering this progressive intellectual failure. The disease was first described by the German psychiatrist, Alois Alzheimer in 1907, and is characterised by the appearance of proteinaceous depositions (first isolated in 1984), which are comprised of insoluble amyloid-ß (Aß)-aggregates. Aβ is derived from the β-amyloid precursor protein from which it is generated by the action of two proteases. Initially it was assumed that the insoluble amyloid fibrils, which were easily detectable, mediated the observed toxicity although it was recognised that amyloid plaque number did not correlate well with the severity of dementia. However, further studies with synthetic and human-derived Aß provided strong evidence that soluble prefibrillar aggregates of Aß mediated the synaptic failure and loss of cognitive performance. In 2008 genetic evidence showed that the presence of soluble Aß-oligomers is sufficient to cause an AD-like dementia, which centres the oligomeric Aβ as the probable effector of synapse loss. Although a variety of assemblies have been described their meta-stability and technical limitations caused a controversial debate about aggregate related pathogenesis. Thus, this study aimed to establish a structure-activity relationship comparing different synthetic Aß-aggregates using biophysical methods to follow aggregation and to assess morphology, absolute MW and meta-stability of monomeric, oligomeric, protofibrillar and fibrillar Aß. However, interference with the aggregate equilibrium, by changing the ionic environment, can cause structural conversion of Aß-aggregates. Therefore, different Aß-aggregates were only compared in short-termed physiological settings i.e. neuronal binding and hippocampal neurotransmission. Herein, only prefibrillar aggregates bound to neurons and differentially impaired hippocampal neurotransmission either by inhibition of basal neurotransmission or NMDA-dependent long-term potentiation. In addition, changing the ionic environment provoked a structural conversion, which also changed the pathogenic mode of action. This study provides experimental evidence that different soluble Aß-aggregates are highly potent synaptotoxins, impairing neurotransmission by different mechanisms. Furthermore, solution-based biophysical characterisation and acute biological paradigms are crucial for differential characterisation of Aß-aggregates revealing that virtually similar aggregates can have opponent pathogenic effects; thus, morphology only does not explain observed pathogenicity.

Direct to consumer (DTC) personal genetic testing (PGT) is a popular choice for individuals in the United States who are interested in learning more about their genetic health risks without formally seeing a medical professional. The company 23andMe offers FDA-approved genetic risk tests for conditions including late-onset Alzheimer’s Disease (AD), Parkinson Disease, Celiac Disease, and the BRCA1/2 mutations. Although this company’s genetic risk testing results are accompanied by a generic information sheet regarding what each individual’s result means for each condition, formal genetic counseling is not included in the service. However, when a condition such as late-onset AD has both known genetic and behavioral risk factors, counseling becomes essential in preventing or delaying disease onset. Following a Mediterranean-style diet, regularly exercising, and regularly participating in cognitive activities (e.g. reading the newspaper or playing a musical instrument) are each thought to be protective against developing late-onset AD. Previous studies have shown that customers do not usually make significant lifestyle modifications after completing DTC PGT, though the majority of this literature may not be relevant to late-onset AD as it included customers of DTC PGT companies that no longer exist today and the genetic risk test for late-onset AD at that time was not yet approved by the Food and Drug Administration. The proposed study is an interventional study that will compare DTC PGT customer exercise, diet, and cognitive activity habits before and after a personalized genetics counseling session. Exercise will be measured using the Godin-Leisure Time Exercise Questionnaire. Diet will be evaluated by a validated food frequency questionnaire evaluating daily servings of fruits, vegetables, and unprocessed nuts. Cognitive activity at the time of survey will be evaluated by a questionnaire asking for the frequency of various cognitive activities, such as reading newspapers, reading books, artistic activities, and social activities.

The generation of amyloid-β (Aβ) peptides through proteolytic processing of the amyloid precursor protein (APP) is a key pathogenic event in Alzheimer’s disease (AD). Aβ generation begins with APP endocytosis, which is mediated by the endocytic YENPTY sequence located in the cytoplasmic tail of APP. Mints, a family of cytosolic adaptor proteins, directly bind to the YENPTY motif of APP and facilitate APP endocytosis and amyloidogenic processing. In addition, loss of any one of the three Mint proteins decreases Aβ production in aging mouse models of AD, supporting the hypothesis that the APP-Mint interaction may provide a novel therapeutic target to selectively reduce Aβ production in AD. Characterizing the biochemical and cellular dynamics of the APP-Mint interaction is critical for understanding Aβ generation. Thus, we generated Mint1 mutants that bind with high affinity (Mint1Y633A) or low affinity (Mint1Y549A/F610A) to APP. These Mint1 mutants exhibited profound alterations in cellular localization, APP endocytosis, and Aβ production. Therapeutically, we generated a novel cell-permeable APP mimetic peptide (APPMP) that interferes with the APP-Mint interaction. This APPMP was designed to outcompete endogenous APP binding, with a 46-fold improved affinity to Mint. Treatment of primary neurons from an AD mouse model with several cell permeable APPMP variants reduced Aβ production with minimal cellular toxicity, supporting Mints as a promising novel therapeutic target for AD. The PTB domain of Mint1 that mediates APP binding is autoinhibited by an adjacent C-terminal α-helix. However, the molecular mechanisms underlying the relief of Mint1 autoinhibition are unclear. Since post-translational modification is one mechanism for alleviating protein autoinhibition, and Mint1 is highly regulated by phosphorylation, we performed mass spectrometry and identified several Mint1 phosphosites. In addition, we found constitutively-active Src kinase, a kinase implicated in Mint phosphorylation, enhanced APP-Mint1 binding. These results suggest that Src kinase-mediated phosphorylation of Mint1 may relieve Mint1 autoinhibition and promote APP-Mint1 interaction. Overall, this work biochemically characterized the Mint-APP interaction and how it affects amyloidogenic processing, provided a proof of concept for targeting the APP-Mint1 interaction as an AD therapeutic target, and suggested a novel mechanism for the relief of Mint1 autoinhibition.

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Yes / The perspectives of people with moderate-to-severe dementia are rarely directly elicited in research studies. Objectives: This systematic review will explore methods and approaches for including the perspectives and preferences of people with moderate-to-severe dementia in research. Methods: AgeLine, CINAHL, Embase, PsycINFO, PubMed, Social Policy and Practice and Web of Science were searched until June 16 2022. Study quality was assessed using the 16-item Quality Assessment Tool. We described specific communication tools, reviewed the evidence for their effectiveness and considered their strengths and limitations. We examined the more general communication skills and techniques applied to support the use of these tools using thematic synthesis. The review protocol was registered with PROSPERO CRD42019130386 and the review was conducted and reported according to PRISMA guidelines. Results: Seven studies reported in 11 publications were included. In these studies five specific communication tools were used: Talking Mats, Augmentative and Alternative Communication Flexiboard, generic photographs in combination with a preference placement board, consultation ballot and personalised communication prescriptions. Each tool identified had advantages and disadvantages depending on dementia severity, verbal or physical ability, expense, researcher training requirements and ease of use. Thematic synthesis identified five general approaches to optimising communication that were employed to support use of the tools: ensuring conversations are individual and person-centred, managing external influences, engaging others, creating structure and facilitation skills. Conclusion: All tools had some utility and there was no clear evidence to support the recommendation of any one specific tool; therefore, researchers are advised to select the tool most appropriate to their context. Implications for Practice: The findings offer general guidance for researchers and practitioners on how to facilitate communication with people with moderate-to-severe dementia. / Alzheimer's Society. Grant Number: AS-PR2-16-001. National Institute for Health and Care Research. Grant Number: ES/L001853/2. UK Research and Innovation. Grant Number: ES/L001853/2

Specific mutations in the gene for the beta amyloid precursor protein (APP) cause Alzheimer's disease (AD). A key neuropathological hallmark of AD is extracellular neuritic plaques. The core component of plaques is AB, a 39-43 amino acid peptide derived from APP. APP C-100 and APP C-105 are C-terminal fragments of APP, 100 and 105 amino acids long, respectively. APP C-100 is a normal metabolite of APP. AI3 is located at the N-terminus of the APP C-100 sequence. To determine whether APP C-105 expression alters cellular vulnerability to calcium and hydrogen peroxide, rat PC12 cells were modified to overexpress APP C-105. Permanent transfectants (clones) were selected, then characterized by standard molecular biological techniques. DNA and mRNA corresponding to APP C-105 were detected in APP C-105 transfectants, but not in wild type controls. Aggregated APP C-105 was detected in cell lysates and conditioned media from APP C-105 transfectants, but was absent or detected at lower concentrations in vector-transfected and wild type controls. Cell survival as a function of concentration was determined for A23 l 87, a Ca^2+ ionophore, and hydrogen peroxide in APP C-105 transfectants and vector-transfected controls. Cells were exposed to A23 l 87 or hydrogen peroxide for 24 hours in RP:MI media containing 3 μM insulin, and survival was quantitated using the tetrazolium dye, MTT. APP C-105 expression significantly increased PC 12 cell vulnerability to A23 l 87, and significantly decreased vulnerability to hydrogen peroxide. Other experiments were performed with GM 1 ganglioside, which is known to protect cells against numerous insults. When wild type PC 12 cells or APP C-10 5 transfectants were exposed to a toxin and GMl concurrently for 24 hours, GMl produced concentration-dependent inhibition of A23 l 87 toxicity in wild type PC 12 cells but was ineffective against hydrogen peroxide in both wild type PC12 and APP C-105-transfected clones. The current study has demonstrated that expression of APP C-105 protects PC 12 cells against hydrogen peroxide, but exacerbates the effect of calcium influx. In conjunction with other reports, this study indicates that APP C-105 is an important regulator of cellular homeostasis. Therefore, the pattern of APP processing may alter vulnerability to neurotoxic insults.

Thesis (Ph. D.)--University of Michigan, 1995. / eContent provider-neutral record in process. Description based on print version record.