A molecular view of human amyloid-β folds

Science ◽  
2022 ◽  
Vol 375 (6577) ◽  
pp. 147-148
Author(s):  
Michael Willem ◽  
Marcus Fändrich
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Disease Modifying

Structures of amyloid-β fibrils suggest Alzheimer’s disease–modifying strategies

Disease modifying strategies for the treatment of Alzheimer's disease targeted at modulating levels of the β-amyloid peptide

2005 ◽  
Vol 33 (4) ◽  
pp. 553-558 ◽  
Author(s):  
M.N. Pangalos ◽  
S.J. Jacobsen ◽  
P.H. Reinhart
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Cell Death ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Proteolytic Processing ◽  
Amyloid Peptide ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid ◽  
Disease Modifying

AD (Alzheimer's disease) is characterized neuropathologically by the presence of amyloid plaques, neurofibrillary tangles and profound grey matter loss. The ‘amyloid’ hypothesis postulates that the toxic Aβ (amyloid β) peptide, enzymatically derived from the proteolytic processing of a larger protein called APP (amyloid precursor protein), is one of the principal causative factors of neuronal cell death in the brains of AD patients. As such, methods for lowering Aβ levels in the brain are of significant interest with regard to identifying novel disease modifying therapies for the treatment of AD. In this review, we will review a variety of approaches and mechanisms capable of modulating levels of Aβ.

Alzheimer's Disease: Progress in the Development of Anti-amyloid Disease-Modifying Therapies

CNS Spectrums ◽  
2007 ◽  
Vol 12 (2) ◽  
pp. 113-123 ◽  
Author(s):  
Daniel D. Christensen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Amyloid Β ◽  
Phase Iii ◽  
Peroxisome Proliferator ◽  
Serious Adverse Events ◽  
Amyloid Disease ◽  
Aβ Aggregation ◽  
Disease Modifying

ABSTRACTThe amyloid hypothesis—the leading mechanistic theory of Alzheimer's disease—states that an imbalance in production or clearance of amyloid β (Aβ) results in accumulation of Aβ and triggers a cascade of events leading to neurodegeneration and dementia. The number of persons with Alzheimer's disease is expected to triple by mid-century. If steps are not taken to delay the onset or slow the progression of Alzheimer's disease, the economic and personal tolls will be immense. Different classes of potentially disease-modifying treatments that interrupt early pathological events (ie, decreasing production or aggregation of Aβ or increasing its clearance) and potentially prevent downstream events are in phase II or III clinical studies. These include immunotherapies; secretase inhibitors; selective Aβ42-lowering agents; statins; anti-Aβ aggregation agents; peroxisome proliferator-activated receptor-gamma agonists; and others. Safety and serious adverse events have been a concern with immunotherapy and γ-secretase inhibitors, though both continue in clinical trials. Anti-amyloid disease-modifying drugs that seem promising and have reached phase III clinical trials include those that selectively target Aβ42 production (eg, tarenflurbil), enhance the activity of α-secretase (eg, statins), and block Aβ aggregation (eg, transiposate).

scholarly journals The Role of Lysosomes in a Broad Disease-Modifying Approach Evaluated across Transgenic Mouse Models of Alzheimer’s Disease and Parkinson’s Disease and Models of Mild Cognitive Impairment

2019 ◽  
Vol 20 (18) ◽  
pp. 4432 ◽  
Author(s):  
Jeannie Hwang ◽  
Candice M. Estick ◽  
Uzoma S. Ikonne ◽  
David Butler ◽  
Morgan C. Pait ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Amyloid Β ◽  
Age Related ◽  
Disease Modifying

Many neurodegenerative disorders have lysosomal impediments, and the list of proposed treatments targeting lysosomes is growing. We investigated the role of lysosomes in Alzheimer’s disease (AD) and other age-related disorders, as well as in a strategy to compensate for lysosomal disturbances. Comprehensive immunostaining was used to analyze brains from wild-type mice vs. amyloid precursor protein/presenilin-1 (APP/PS1) mice that express mutant proteins linked to familial AD. Also, lysosomal modulation was evaluated for inducing synaptic and behavioral improvements in transgenic models of AD and Parkinson’s disease, and in models of mild cognitive impairment (MCI). Amyloid plaques were surrounded by swollen organelles positive for the lysosome-associated membrane protein 1 (LAMP1) in the APP/PS1 cortex and hippocampus, regions with robust synaptic deterioration. Within neurons, lysosomes contain the amyloid β 42 (Aβ42) degradation product Aβ38, and this indicator of Aβ42 detoxification was augmented by Z-Phe-Ala-diazomethylketone (PADK; also known as ZFAD) as it enhanced the lysosomal hydrolase cathepsin B (CatB). PADK promoted Aβ42 colocalization with CatB in lysosomes that formed clusters in neurons, while reducing Aβ deposits as well. PADK also reduced amyloidogenic peptides and α-synuclein in correspondence with restored synaptic markers, and both synaptic and cognitive measures were improved in the APP/PS1 and MCI models. These findings indicate that lysosomal perturbation contributes to synaptic and cognitive decay, whereas safely enhancing protein clearance through modulated CatB ameliorates the compromised synapses and cognition, thus supporting early CatB upregulation as a disease-modifying therapy that may also slow the MCI to dementia continuum.

Cognitive symptoms of Alzheimer’s disease: clinical management and prevention

BMJ ◽  
2019 ◽  
pp. l6217 ◽  
Author(s):  
Elizabeth Joe ◽  
John M Ringman
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Acetylcholinesterase Inhibitors ◽  
Amyloid Cascade Hypothesis ◽  
Prodromal Ad ◽  
Disease Modifying ◽  
Medical Foods ◽  
Disease Modifying Treatment ◽  
Amyloid Cascade

ABSTRACTAlzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of amyloid β in the form of extracellular plaques and by intracellular neurofibrillary tangles, with eventual neurodegeneration and dementia. There is currently no disease-modifying treatment though several symptomatic medications exist with modest benefit on cognition. Acetylcholinesterase inhibitors have a consistent benefit across all stages of dementia; their benefit in mild cognitive impairment and prodromal AD is unproven. Memantine has a smaller benefit on cognition overall which is limited to the moderate to severe stages, and the combination of a cholinesterase inhibitor and memantine may have additional efficacy. Evidence for the efficacy of vitamin E supplementation and medical foods is weak but might be considered in the context of cost, availability, and safety in individual patients. Apparently promising disease-modifying interventions, mostly addressing the amyloid cascade hypothesis of AD, have recently failed to demonstrate efficacy so novel approaches must be considered.

scholarly journals Genetic Dissection of Alzheimer’s Disease Using Drosophila Models

2020 ◽  
Vol 21 (3) ◽  
pp. 884 ◽  
Author(s):  
Youngjae Jeon ◽  
Jae Ha Lee ◽  
Byoungyun Choi ◽  
So-Yoon Won ◽  
Kyoung Sang Cho
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Genetic Model ◽  
Amyloid Β ◽  
Genetic Dissection ◽  
Abnormal Accumulation ◽  
Disease Modifying ◽  
Disease Modifying Treatment ◽  
Drosophila Models

Alzheimer’s disease (AD), a main cause of dementia, is the most common neurodegenerative disease that is related to abnormal accumulation of the amyloid β (Aβ) protein. Despite decades of intensive research, the mechanisms underlying AD remain elusive, and the only available treatment remains symptomatic. Molecular understanding of the pathogenesis and progression of AD is necessary to develop disease-modifying treatment. Drosophila, as the most advanced genetic model, has been used to explore the molecular mechanisms of AD in the last few decades. Here, we introduce Drosophila AD models based on human Aβ and summarize the results of their genetic dissection. We also discuss the utility of functional genomics using the Drosophila system in the search for AD-associated molecular mechanisms in the post-genomic era.

scholarly journals Alzheimer’s disease: A clinical perspective and future nonhuman primate research opportunities

2019 ◽  
Vol 116 (52) ◽  
pp. 26224-26229 ◽  
Author(s):  
Rafi U. Haque ◽  
Allan I. Levey
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nonhuman Primate ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Primate Research ◽  
Physiological Mechanisms ◽  
Diagnostic Approaches ◽  
Disease Modifying

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is the sixth leading cause of death and the most common cause of dementia worldwide. Over the last few decades, significant advancements have been made in our understanding of AD by investigating the molecular mechanisms underlying amyloid-β and tau pathology. Despite this progress, no disease-modifying treatments exist for AD, an issue that will exacerbated by the rising costs and prevalence of the disorder. Moreover, effective therapies to address the devastating cognitive and behavioral symptoms are also urgently needed. This perspective focuses on the value of nonhuman primate (NHP) models in bridging the molecular, circuit, and behavioral levels of analysis to better understand the complex genetic and environmental/lifestyle factors that contribute to AD pathogenesis. These investigations could provide an opportunity for translating our understanding of the pathogenesis and physiological mechanisms underlying AD and related disorders into new diagnostic approaches and disease-modifying therapies to prevent disease or restore brain function for symptomatic individuals.

scholarly journals Altered Cortical and Hippocampal Excitability in TgF344-AD Rats Modeling Alzheimer’s Disease Pathology

2018 ◽  
Vol 29 (6) ◽  
pp. 2716-2727 ◽  
Author(s):  
Milan Stoiljkovic ◽  
Craig Kelley ◽  
Bernardo Stutz ◽  
Tamas L Horvath ◽  
Mihály Hajós
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Synaptic Function ◽  
Quiescent State ◽  
Theta Oscillation ◽  
Age Dependent ◽  
Disease Modifying ◽  
Hippocampal Theta

Abstract Current findings suggest that accumulation of amyloid-β (Aβ) and hyperphosphorylated tau in the brain disrupt synaptic function in hippocampal–cortical neuronal networks leading to impairment in cognitive and affective functions in Alzheimer’s disease (AD). Development of new disease-modifying AD drugs are challenging due to the lack of predictive animal models and efficacy assays. In the present study we recorded neural activity in TgF344-AD rats, a transgenic model with a full array of AD pathological features, including age-dependent Aβ accumulation, tauopathy, neuronal loss, and cognitive impairments. Under urethane anesthesia, TgF344-AD rats showed significant age-dependent decline in brainstem-elicited hippocampal theta oscillation and decreased theta-phase gamma-amplitude coupling comparing to their age-matched wild-type counterparts. In freely-behaving condition, the power of hippocampal theta oscillation and gamma power during sharp-wave ripples were significantly lower in TgF344-AD rats. Additionally, these rats showed impaired coherence in both intercortical and hippocampal–cortical network dynamics, and increased incidence of paroxysmal high-voltage spindles, which occur during awake, behaviorally quiescent state. TgF344-AD rats demonstrated impairments in sensory processing, having diminished auditory gating and 40-Hz auditory evoked steady-state response. The observed differences in neurophysiological activities in TgF344-AD rats, which mirror several abnormalities described in AD patients, may be used as promising markers to monitor disease-modifying therapies.

Introduction: The Prevalence of Alzheimer's Disease — A Growing Crisis

CNS Spectrums ◽  
2008 ◽  
Vol 13 (S3) ◽  
pp. 3-3
Author(s):  
Stephen Salloway
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Neuritic Plaques ◽  
Mental Deterioration ◽  
Β Protein ◽  
Alois Alzheimer ◽  
Disease Modifying ◽  
German Physician

In 1906, the German physician Alois Alzheimer provided the first description of the “serious and peculiar disease” of mental deterioration that would later on take his name. Alzheimer described the classic pathology of neuritic plaques and neurofibrillary tangles in an affected patient. Since that time, understanding of Alzheimer's disease (AD) has progressed substantially, although the ability to influence disease progression has not progressed as rapidly. It is likely that over the next decade these advances will lead to earlier diagnosis and development of disease-modifying treatments for AD.It is known that two variants of AD exist: a rare hereditary form and a more prevalent sporadic form. As with many neurodegenerative diseases, early clues to the pathology of AD came from the inherited form of the disease. Hereditary links include mutations of the amyloid precursor protein (APP) and the presenilins, both of which are integrally involved in the cascade of events that leads to the deposition of the 42-amino-acid amyloid β protein and the eventual cell death responsible for AD.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Strong Support ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
Sequence Of Events ◽  
Aβ Amyloid ◽  
Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

Minimalistic Design Approach for Multi-Reactivity against Free Radicals and Metal-Free and Metal-Bound Amyloid-β Peptides: Redox-Based Substitutions of Benzene

2019 ◽  
Author(s):  
Mingeun Kim ◽  
Juhye Kang ◽  
Misun Lee ◽  
Jiyeon Han ◽  
Geewoo Nam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Free Radicals ◽  
Amyloid Β ◽  
Design Strategy ◽  
Design Approach ◽  
Metal Free

We report a minimalistic redox-based design strategy for engineering compact molecules based on the simplest aromatic framework, benzene, with multi-reactivity against free radicals, metal-free amyloid-β, and metal-bound amyloid-β, implicated in the most common form of dementia, Alzheimer’s disease.

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