Half a century of amyloids: past, present and future

Chemical Society Reviews, Год журнала: 2020, Номер 49(15), С. 5473 - 5509

Опубликована: Янв. 1, 2020

Amyloid diseases are global epidemics with profound health, social and economic implications yet remain without a cure. This dire situation calls for research into the origin pathological manifestations of amyloidosis to stimulate continued development new therapeutics. In basic science engineering, cross-β architecture has been constant thread underlying structural characteristics functional amyloids, realizing that amyloid structures can be both in nature fuelled innovations artificial whose use today ranges from water purification 3D printing. At conclusion half century since Eanes Glenner's seminal study amyloids humans, this review commemorates occasion by documenting major milestones date, perspectives biology, biophysics, medicine, microbiology, engineering nanotechnology. We also discuss challenges opportunities drive interdisciplinary field moving forward.

Язык: Английский

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Alzheimer's disease: Recent treatment strategies

European Journal of Pharmacology, Год журнала: 2020, Номер 887, С. 173554 - 173554

Опубликована: Сен. 14, 2020

Язык: Английский

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α-synuclein in the pathophysiology of Alzheimer’s disease

Molecular Neurodegeneration, Год журнала: 2019, Номер 14(1)

Опубликована: Июнь 11, 2019

The Alzheimer's disease (AD) afflicted brain is neuropathologically defined by extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau protein. However, accumulating evidence suggests that the presynaptic protein α-synuclein (αSyn), mainly associated with synucleinopathies like Parkinson's (PD), dementia Lewy bodies (DLB) multiple system atrophy (MSA), involved in pathophysiology AD. Lewy-related pathology (LRP), primarily comprised αSyn, present a majority autopsied AD brains, higher levels αSyn cerebrospinal fluid (CSF) patients mild cognitive impairment (MCI) have been linked to decline. Recent studies also suggest asymptomatic accumulation Aβ CSF subjects at risk sporadic individuals carrying autosomal dominant mutations. Experimental has further hyperphosphorylation, but pathological actions APOEε4 allele, latter being major genetic factor for both DLB. In this review, we provide summary current proposing an involvement either as active or passive player pathophysiological ensemble AD, furthermore describe detail knowledge structure inferred function.

Язык: Английский

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Alzheimer’s Disease: Treatment Strategies and Their Limitations

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(22), С. 13954 - 13954

Опубликована: Ноя. 12, 2022

Alzheimer’s disease (AD) is the most frequent case of neurodegenerative and becoming a major public health problem all over world. Many therapeutic strategies have been explored for several decades; however, there still no curative treatment, priority remains prevention. In this review, we present an update on clinical physiological phase AD spectrum, modifiable non-modifiable risk factors treatment with focus prevention strategies, then research models used in AD, followed by discussion limitations. The methods can significantly slow evolution are currently best strategy possible before advanced stages disease. Indeed, current drug treatments only symptomatic effects, disease-modifying not yet available. Drug delivery to central nervous system complex process represents challenge developing preventive strategies. Studies underway test new techniques facilitate bioavailability molecules brain. After deep study literature, find use soft nanoparticles, particular nanoliposomes exosomes, as innovative approach reducing solving problems brain bioavailability. show promising role exosomes smart systems able penetrate blood–brain barrier target tissues. Finally, different administration neurological disorders discussed. One intranasal which should be preclinical studies diseases.

Язык: Английский

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Alzheimer Disease Pathogenesis: Insights From Molecular and Cellular Biology Studies of Oligomeric Aβ and Tau Species

Frontiers in Neuroscience, Год журнала: 2019, Номер 13

Опубликована: Июнь 21, 2019

Alzheimer disease (AD) represents an oncoming epidemic that without effective treatment promises to exact extraordinary human and financial burdens. Studies of pathogenesis are essential for defining targets discovering disease-modifying treatments. Past studies AD neuropathology provided valuable, albeit limited, insights. Nevertheless, building on these findings, recent have increasingly rich harvest genetic, molecular cellular data creating unprecedented opportunities both understand treat AD. Among the most significant those documenting presence within brain toxic oligomeric species Aβ tau. Existing support view such can propagate spread neural circuits. To place findings in context we first review genetics AD, including Down syndrome. We detail existence while noting unanswered questions concerning their precise structures, means by which they undergo amplification how induce neuronal dysfunction degeneration. conclude offering a speculative synthesis oligomers tau initiate drive pathogenesis. While 100 years after Alzheimer's report there is much still learn about discovery treatments, application new concepts sophisticated tools poised deliver important advances combatting

Язык: Английский

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The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease

Alzheimer s Research & Therapy, Год журнала: 2020, Номер 12(1)

Опубликована: Март 2, 2020

Abstract Background Synapse damage and loss are fundamental to the pathophysiology of Alzheimer’s disease (AD) lead reduced cognitive function. The goal this review is address challenges forging new clinical development approaches for AD therapeutics that can demonstrate reduction synapse or loss. key points include following: a downstream effect amyloidosis, tauopathy, inflammation, other mechanisms occurring in AD. correlates most strongly with decline because synaptic function underlies performance. Compounds halt reduce have strong rationale as treatments Biomarkers measure degeneration patients will facilitate such drugs. ability methods sensitively density brain living patient through vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, concentrations proteins (e.g., neurogranin synaptotagmin) cerebrospinal fluid (CSF), functional imaging techniques quantitative electroencephalography (qEEG) provides compelling case use these types measurements biomarkers quantify trials Conclusion A number emerging able injury may correlate These hold promise both diagnostics measurement therapeutic successes.

Язык: Английский

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The path forward in Alzheimer's disease therapeutics: Reevaluating the amyloid cascade hypothesis

Alzheimer s & Dementia, Год журнала: 2019, Номер 16(11), С. 1553 - 1560

Опубликована: Ноя. 6, 2019

Abstract Development of disease‐modifying treatments for Alzheimer's disease (AD) has been challenging, with no drugs approved to date. The failures several amyloid‐targeted programs have led many dismiss the amyloid beta (Aβ) hypothesis AD. An antiamyloid antibody aducanumab recently showed modest but significant efficacy in a phase 3 trial, providing important validation as therapeutic target. However, inconsistent results observed may be explained by limited brain penetration and lack selectivity soluble Aβ oligomers, which are implicated upstream drivers neurodegeneration multiple studies. agents that can effectively inhibit oligomer formation or block their toxicity is therefore warranted. ideal drug would cross blood‐brain barrier efficiently achieve sustained levels continuously prevent toxicity. A late‐stage candidate these attributes ALZ‐801, an oral favorable safety profile high robustly formation. upcoming trial ALZ‐801 APOE4/4 homozygous patients early AD will test this hypothesis.

Язык: Английский

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Questions concerning the role of amyloid-β in the definition, aetiology and diagnosis of Alzheimer’s disease

Acta Neuropathologica, Год журнала: 2018, Номер 136(5), С. 663 - 689

Опубликована: Окт. 22, 2018

The dominant hypothesis of Alzheimer's disease (AD) aetiology, the neuropathological guidelines for diagnosing AD and majority high-profile therapeutic efforts, in both research clinical practice, have been built around one possible causal factor, amyloid-β (Aβ). However, link between Aβ remains unproven. Here, context a detailed assessment historical contemporary studies, we raise critical questions regarding role definition, diagnosis aetiology AD. We illustrate that holistic view available data does not support an unequivocal conclusion has central or unique Instead, suggest alternative views are potentially valid, at this time. propose unbiased way forward field, beyond current Aβ-centric approach, without excluding Aβ, is required to come accurate understanding dementia and, ultimately, effective treatment.

Язык: Английский

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Simulation Studies of Amyloidogenic Polypeptides and Their Aggregates

Chemical Reviews, Год журнала: 2019, Номер 119(12), С. 6956 - 6993

Опубликована: Апрель 11, 2019

Amyloids, fibrillar assembly of (poly)peptide chains, are associated with neurodegenerative illnesses such as Alzheimer's and Parkinson's diseases, for which there no cures. The molecular mechanisms the formation toxic species still elusive. Some peptides proteins can form functional amyloid-like aggregates mainly in bacteria fungi but also humans. Little is known on differences self-assembly pathogenic (poly)peptides. We review atomistic coarse-grained simulation studies amyloid their monomeric, oligomeric, states. Particular emphasis given to challenges one faces characterize at atomic level detail conformational space disordered (poly)peptides aggregation. discuss difficulties comparing results experimental data, we propose new shed light aggregation processes diseases.

Язык: Английский

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Proteomic landscape of Alzheimer’s Disease: novel insights into pathogenesis and biomarker discovery

Molecular Neurodegeneration, Год журнала: 2021, Номер 16(1)

Опубликована: Авг. 12, 2021

Mass spectrometry-based proteomics empowers deep profiling of proteome and protein posttranslational modifications (PTMs) in Alzheimer's disease (AD). Here we review the advances limitations historic recent AD proteomic research. Complementary to genetic mapping, studies not only validate canonical amyloid tau pathways, but also uncover novel components broad networks, such as RNA splicing, development, immunity, membrane transport, lipid metabolism, synaptic function, mitochondrial activity. Meta-analysis seven datasets reveals 2,698 differentially expressed (DE) proteins landscape brain (n = 12,017 proteins/genes), covering 35 reported genes risk loci. The DE contain cellular markers enriched neurons, microglia, astrocytes, oligodendrocytes, epithelial cells, supporting involvement diverse cell types pathology. We discuss hypothesized protective or detrimental roles selected proteins, emphasizing top "amyloidome" (all biomolecules plaques) progression. Comprehensive PTM analysis represents another layer molecular events AD. In particular, PTMs are correlated with stages indicate heterogeneity individual patients. Moreover, unprecedented coverage biofluids, cerebrospinal fluid serum, procures putative biomarkers through meta-analysis. Thus, proteomics-driven systems biology presents a new frontier link genotype, proteotype, phenotype, accelerating development improved models treatment strategies.

Язык: Английский

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