Deposition of amyloid β in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Год журнала: 2015, Номер 1862(5), С. 1037 - 1046

Опубликована: Авг. 29, 2015

Deposition of amyloid β (Aβ) in the walls cerebral arteries as angiopathy (CAA) suggests an age-related failure perivascular drainage soluble Aβ from brain. As CAA is associated with Alzheimer's disease and intracerebral haemorrhage, present study determines unique sequence changes that occur accumulates artery walls. Paraffin sections post-mortem human occipital cortex were immunostained for collagen IV, fibronectin, nidogen 2, smooth muscle actin immunostaining was analysed using Image J confocal microscopy. Results showed 2 (entactin) increases age decreases CAA. Confocal microscopy revealed stages progression CAA: initially deposits basement membranes tunica media, replaces first cells then connective tissue elements to leave completely or focally replaced by Aβ. The pattern development brain expansion progressively replace all wall. Establishing this full picture pivotal understanding clinical presentation developing therapies prevent accumulation This article part a Special Issue entitled: Vascular Contributions Cognitive Impairment Dementia edited M. Paul Murphy, Roderick A. Corriveau Donna Wilcock.

Язык: Английский

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The Important Interface Between Apolipoprotein E and Neuroinflammation in Alzheimer’s Disease

Frontiers in Immunology, Год журнала: 2020, Номер 11

Опубликована: Апрель 30, 2020

Alzheimer's disease (AD) is the most prevalent form of neurodegenerative disease, currently affecting over 5 million Americans with projections expected to rise as population ages. The hallmark pathologies AD are Aplaques composed aggregated beta-amyloid (A), and tau tangles hyperphosphorylated, tau. These typically accompanied by an increase in neuroinflammation attempt ameliorate pathology. This idea has pushed field towards focusing on mechanisms influence progression. vast majority cases sporadic therefore, researchers investigate genetic risk factors that could lead AD. Apolipoprotein E (ApoE) largest factor for developing ApoE 3 isoforms- ApoE2, ApoE3, ApoE4. ApoE4 constitutes increased AD, one copy increasing about 4-fold two copies 15-fold compared those ApoE3 allele. been shown play a role Adeposition, tangle formation, many subsequent pathways. However, while we know plays these pathways virtually all aspects exact mechanism how impacts progression murky at best therefore needs be elucidated. review aims discuss current literature regarding focus its neuroinflammation.

Язык: Английский

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Amyloid β-peptides interfere with mitochondrial preprotein import competence by a coaggregation process

Molecular Biology of the Cell, Год журнала: 2016, Номер 27(21), С. 3257 - 3272

Опубликована: Сен. 15, 2016

Aβ peptides play a central role in the etiology of Alzheimer disease (AD) by exerting cellular toxicity correlated with aggregate formation. Experimental evidence has shown intraneuronal accumulation and interference mitochondrial functions. Nevertheless, relevance intracellular pathophysiology AD is controversial. Here we found that two major species peptides, particular Aβ42, exhibited strong inhibitory effect on preprotein import reactions essential for biogenesis. However, interacted only weakly mitochondria did not affect inner membrane potential or structure translocase complexes. significantly decreased competence precursor proteins via an extramitochondrial coaggregation mechanism. Coaggregation inhibition were stronger longer peptide correlating its importance pathology. Our results demonstrate direct aggregation-prone protein biogenesis represents crucial aspect pathobiochemical mechanisms contributing to damage AD.

Язык: Английский

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The human olfactory system in two proteinopathies: Alzheimer’s and Parkinson’s diseases

Translational Neurodegeneration, Год журнала: 2020, Номер 9(1)

Опубликована: Июнь 3, 2020

Alzheimer's and Parkinson's diseases are the most prevalent neurodegenerative disorders. Their etiologies idiopathic, treatments symptomatic orientated towards cognitive or motor deficits. Neuropathologically, both proteinopathies with pathological aggregates (plaques of amyloid-β peptide neurofibrillary tangles tau protein in disease, Lewy bodies mostly composed α-synuclein disease). These deposits appear nervous system a predictable accumulative sequence six neuropathological stages. Both disorders present long prodromal period, characterized by preclinical signs including hyposmia. Interestingly, olfactory system, particularly anterior nucleus, is initially preferentially affected pathology. Cerebral atrophy revealed magnetic resonance imaging must be complemented histological analyses to ascertain whether neuronal and/or glial loss neuropil remodeling responsible for volumetric changes. It has been proposed that these could act prion-like manner which misfolded would able force native proteins into pathogenic folding (seeding), then propagates through neurons glia (spreading). Existing data have examined establish why some populations vulnerable while others resistant pathology what extent prevent facilitate proteinopathy spreading. Connectomic approaches reveal number hubs (anterior entorhinal cortex cortical amygdala) key interconnectors main (the entorhinal-hippocampal-cortical amygdala-dorsal vagal nucleus) network dysfunction diseases.

Язык: Английский

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Critical Appraisal of Amyloid Lowering Agents in AD

Current Neurology and Neuroscience Reports, Год журнала: 2021, Номер 21(8)

Опубликована: Июнь 10, 2021

Abstract Purpose of Review According to the amyloid cascade hypothesis, removing beta (Aβ) should cure Alzheimer’s disease (AD). In past three decades, many agents have been tested try lower Aβ production, prevent aggregation, and dissolve deposits. However, paucity in definitive preventative or curative properties these clinical trials has resulted more avant-garde approaches therapeutic investigations. Immunotherapy become an area focus for research on disease-modifying therapies neurodegenerative diseases. this review, we highlight current development landscape monoclonal antibody (mAb) that target plaque formation removal AD. Recent Findings Multiple potential therapeutics AD are active development. Targeting with mAbs treat various stages AD: prodromal, prodromal mild, mild moderate. Monoclonal antibodies discussed here include aducanumab, lecanemab, solanezumab, crenezumab, donanemab, gantenerumab. Summary The final decision by FDA regarding approval aducanumab will offer valuable insight into trajectory drug other Future directions improving treatment inquiry efficacy as specifically peptides and/or multimers. addition, a robust trial design immunotherapy improve outcomes such objective measures eventually lead higher chances approval.

Язык: Английский

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New therapeutics beyond amyloid-β and tau for the treatment of Alzheimer’s disease

Acta Pharmacologica Sinica, Год журнала: 2020, Номер 42(9), С. 1382 - 1389

Опубликована: Дек. 2, 2020

Язык: Английский

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CSF and Blood Biomarkers in Neuroinflammatory and Neurodegenerative Diseases: Implications for Treatment

Trends in Pharmacological Sciences, Год журнала: 2020, Номер 41(12), С. 1023 - 1037

Опубликована: Окт. 27, 2020

Язык: Английский

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Neurovascular dysfunction and vascular amyloid accumulation as early events in Alzheimer's disease

Metabolic Brain Disease, Год журнала: 2021, Номер 37(1), С. 39 - 50

Опубликована: Авг. 18, 2021

Язык: Английский

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Role of mutations and post-translational modifications in systemic AL amyloidosis studied by cryo-EM

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Ноя. 5, 2021

Systemic AL amyloidosis is a rare disease that caused by the misfolding of immunoglobulin light chains (LCs). Potential drivers amyloid formation in this are post-translational modifications (PTMs) and mutational changes inserted into LCs somatic hypermutation. Here we present cryo electron microscopy (cryo-EM) structure an ex vivo λ1-AL fibril whose deposits disrupt ordered cardiomyocyte heart. The protein contains six compared to germ line three PTMs (disulfide bond, N-glycosylation pyroglutamylation). Our data imply disulfide glycosylation contribute determining fold help generate morphology able withstand proteolytic degradation inside body.

Язык: Английский

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Targeting NLRP3-Mediated Neuroinflammation in Alzheimer’s Disease Treatment

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(16), С. 8979 - 8979

Опубликована: Авг. 11, 2022

Alzheimer's disease (AD) is the most common cause of dementia in general population and, to date, constitutes a major therapeutic challenge. In pathogenesis AD, aggregates amyloid β (Aβ) and neurofibrillary tangles (NFTs) containing Tau-microtubule-associated protein (tau) are known trigger neuroinflammatory response with subsequent formation an inflammasome. particular, NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome thought play crucial role AD-related pathology. While mechanisms for NLRP3 activation not fully understood, it has been demonstrated that, after detection aggregates, induces pro-inflammatory cytokines, such as interleukin 18 (IL-18) or 1β (IL-1β), that further potentiate AD progression. Specific inhibitors exhibit various attenuate activity have tested vivo studies yielded promising results, shown by reduced level tau Aβ diminished cognitive impairment. Herein, we would like summarize current state knowledge on priming, activation, its actual pathogenesis, characterize studied their impact

Язык: Английский

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