Not just amyloid: physiological functions of the amyloid precursor protein family

Nature reviews. Neuroscience, Journal Year: 2017, Volume and Issue: 18(5), P. 281 - 298

Published: March 31, 2017

Language: Английский

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Amyloid-β and tau complexity — towards improved biomarkers and targeted therapies

Nature Reviews Neurology, Journal Year: 2017, Volume and Issue: 14(1), P. 22 - 39

Published: Dec. 15, 2017

Language: Английский

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The Amyloid Cascade Hypothesis in Alzheimer’s Disease: It’s Time to Change Our Mind

Current Neuropharmacology, Journal Year: 2017, Volume and Issue: 15(6)

Published: July 31, 2017

Since its discovery in 1984, the beta amyloid peptide has treaded boards of neurosciences as star molecule Alzheimer’s disease pathogenesis. In last decade, however, this vision been challenged by evidence-based medicine showing almost complete failure clinical trials that experimented anti-amyloid therapies with great hopes. Moreover, data have accumulated which clearly indicate small plays a key role physiological processes memory formation. present review, we will discuss different aspects cascade hypothesis, highlighting pros and cons, analyse results therapeutic approaches attempted to date should change direction research future. Keywords: Alzheimer's disease, amyloid, trials, LTP, memory, therapy.

Language: Английский

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Comprehensive review of mechanisms of pathogenesis involved in Alzheimer’s disease and potential therapeutic strategies

Progress in Neurobiology, Journal Year: 2018, Volume and Issue: 174, P. 53 - 89

Published: Dec. 30, 2018

Language: Английский

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Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

Frontiers in Physiology, Journal Year: 2020, Volume and Issue: 11

Published: June 9, 2020

Lipids constitute the bulk of dry mass brain and have been associated with healthy function as well most common pathological conditions brain. Demographic factors, genetics, lifestyles are major factors that influence lipid metabolism also key components disruption in Alzheimer's disease (AD). Additionally, genetic risk factor AD, APOE ϵ4 genotype, is involved transport metabolism. We propose lipids at center pathology based on their involvement blood-brain barrier function, amyloid precursor protein (APP) processing, myelination, membrane remodeling, receptor signaling, inflammation, oxidation, energy balance. Under conditions, homeostasis bestows a balanced cellular environment enables proper functioning cells. However, under dyshomeostasis composition can result disturbed BBB, abnormal processing APP, dysfunction endocytosis/exocytosis/autophagocytosis, altered unbalanced metabolism, enhanced inflammation. These disturbances may contribute to abnormalities hallmark AD. The wide variance suggest AD present complex interaction between several metabolic pathways augmented by such age, lifestyles. Herewith, we examine composition, review association all known facets pathology, offer pointers for potential therapies target pathways.

Language: Английский

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VDAC1, mitochondrial dysfunction, and Alzheimer's disease

Pharmacological Research, Journal Year: 2018, Volume and Issue: 131, P. 87 - 101

Published: March 15, 2018

Language: Английский

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Lipid Peroxidation Drives Liquid–Liquid Phase Separation and Disrupts Raft Protein Partitioning in Biological Membranes

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(2), P. 1374 - 1387

Published: Jan. 3, 2024

The peroxidation of membrane lipids by free radicals contributes to aging, numerous diseases, and ferroptosis, an iron-dependent form cell death. Peroxidation changes the structure physicochemical properties lipids, leading bilayer thinning, altered fluidity, increased permeability membranes in model systems. Whether how lipid impacts lateral organization proteins biological membranes, however, remains poorly understood. Here, we employ cell-derived giant plasma vesicles (GPMVs) as a investigate impact on ordered domains, often termed rafts. We show that induced Fenton reaction dramatically enhances phase separation propensity GPMVs into coexisting liquid-ordered (Lo) liquid-disordered (Ld) domains increases relative abundance disordered phase. also leads preferential accumulation peroxidized 4-hydroxynonenal (4-HNE) adducts phase, decreased packing both Lo Ld translocation multiple classes raft out domains. These findings indicate disturbs many aspects rafts, including their stability, abundance, packing, protein composition. propose these disruptions contribute pathological consequences during aging disease thus serve potential targets for therapeutic intervention.

Language: Английский

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Synaptic dysfunction in Alzheimer's disease: the effects of amyloid beta on synaptic vesicle dynamics as a novel target for therapeutic intervention

Neural Regeneration Research, Journal Year: 2018, Volume and Issue: 13(4), P. 616 - 616

Published: Jan. 1, 2018

The most prevalent form of dementia in the elderly is Alzheimer's disease. A significant contributing factor to progression disease appears be progressive accumulation amyloid-β42 (Aβ42), a small hydrophobic peptide. Unfortunately, attempts develop therapies targeting Aβ42 have not been successful treat or even slow down It possible that this failure an indication downstream effects rather than peptide itself might more effective approach. seems affect various aspects physiological cell functions. In review, we provide overview evidence implicates synaptic dysfunction, with focus on how it contributes defects vesicle dynamics and neurotransmitter release. We discuss data new insights induced pathology detailed understanding its contribution deficiencies are associated early stages Although precise mechanisms trigger dysfunction still under investigation, available so far has enabled us put forward model could used as guide generate therapeutic targets for pharmaceutical intervention.

Language: Английский

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Tau Proteolysis in the Pathogenesis of Tauopathies: Neurotoxic Fragments and Novel Biomarkers

Journal of Alzheimer s Disease, Journal Year: 2018, Volume and Issue: 63(1), P. 13 - 33

Published: April 3, 2018

With predictions showing that 131.5 million people worldwide will be living with dementia by 2050, an understanding of the molecular mechanisms underpinning disease is crucial in hunt for novel therapeutics and biomarkers to detect early and/or monitor progression. The metabolism microtubule-associated protein tau altered different dementias, so-called tauopathies. Tau detaches from microtubules, aggregates into oligomers neurofibrillary tangles, which can secreted neurons, spreads through brain during Post-translational modifications exacerbate production both oligomeric soluble forms tau, proteolysis a range proteases being driver. However, impact on progression has been overlooked until recently. Studies have highlighted proteolytic fragments drive neurodegeneration fragment-dependent manner as result aggregation transcellular propagation. Proteolytic found cerebrospinal fluid plasma patients tauopathies, providing opportunity develop these biomarkers. A therapeutic strategies proposed halt toxicity associated proteolysis, including reducing protease expression activity, selectively inhibiting protease-substrate interactions, blocking action resulting fragments. This review highlights importance pathogenesis identifies putative sites fragment-mediated could targeted therapeutically, discusses potential use

Language: Английский

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Cellular and Molecular Mechanisms of Prion Disease

Annual Review of Pathology Mechanisms of Disease, Journal Year: 2018, Volume and Issue: 14(1), P. 497 - 516

Published: Oct. 25, 2018

Prion diseases are rapidly progressive, incurable neurodegenerative disorders caused by misfolded, aggregated proteins known as prions, which uniquely infectious. Remarkably, these infectious have been responsible for widespread disease epidemics, including kuru in humans, bovine spongiform encephalopathy cattle, and chronic wasting cervids, the latter of has spread across North America recently appeared Norway Finland. The hallmark histopathological features include encephalopathy, neuronal loss, gliosis, deposits variably sized prion protein, ranging from small, soluble oligomers to long, thin, unbranched fibrils, depending on disease. Here, we explore recent advances research, function cellular protein dysfunction triggering neurotoxicity, well mechanisms underlying between cells. We also highlight key findings that revealed new therapeutic targets consider unanswered questions future research.

Language: Английский

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