Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature

Journal of Neuropathology & Experimental Neurology, Год журнала: 2012, Номер 71(5), С. 362 - 381

Опубликована: Апрель 6, 2012

Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and validity correlations. Many sources data variability can weaken apparent between cognitive status AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions may alter cognition independently AD. Worldwide research efforts evaluated thousands to assess causes impairment elderly, these been interpreted different ways. We review literature focusing changes (i.e. β-amyloid plaques neurofibrillary tangles) impairment. discuss various patterns observed elderly individuals provide a perspective understanding clinicopathologic conclude evidence from many independent centers strongly supports existence specific disease, as defined by presence Aβ tangles. Although play key role pathogenesis, severity correlates best burden neocortical

Язык: Английский

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Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease

Trends in Molecular Medicine, Год журнала: 2008, Номер 14(2), С. 45 - 53

Опубликована: Янв. 24, 2008

Язык: Английский

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Long-term Air Pollution Exposure Is Associated with Neuroinflammation, an Altered Innate Immune Response, Disruption of the Blood-Brain Barrier, Ultrafine Particulate Deposition, and Accumulation of Amyloid β-42 and α-Synuclein in Children and Young Adults

Toxicologic Pathology, Год журнала: 2008, Номер 36(2), С. 289 - 310

Опубликована: Фев. 1, 2008

Air pollution is a serious environmental problem. We investigated whether residency in cities with high air associated neuroinflammation/neurodegeneration healthy children and young adults who died suddenly. measured mRNA cyclooxygenase-2, interleukin-1β, CD14 target brain regions from low (n = 12) or highly exposed residents 35) aged 25.1 ± 1.5 years. Upregulation of olfactory bulb, frontal cortex, substantia nigrae vagus nerves; disruption the blood-brain barrier; endothelial activation, oxidative stress, inflammatory cell trafficking were seen subjects. Amyloid β42 (Aβ42) immunoreactivity was observed 58.8% apolipoprotein E (APOE) 3/3 < 25 y, 100% APOE 4 subjects, whereas α-synuclein 23.5% y Particulate material (PM) bulb neurons, PM 100 nm intraluminal erythrocytes lung, frontal, trigeminal ganglia capillaries. Exposure to causes neuroinflammation, an altered innate immune response, accumulation Aβ42 starting childhood. should be considered risk factor for Alzheimer’s Parkinson’s diseases, carriers allele could have higher developing disease if they reside polluted environment.

Язык: Английский

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Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins

Proceedings of the National Academy of Sciences, Год журнала: 2008, Номер 105(49), С. 19318 - 19323

Опубликована: Дек. 3, 2008

Mitochondrial dysfunction is a prominent feature of Alzheimer disease but the underlying mechanism unclear. In this study, we investigated effect amyloid precursor protein (APP) and β on mitochondrial dynamics in neurons. Confocal electron microscopic analysis demonstrated that ≈40% M17 cells overexpressing WT APP (APPwt cells) more than 80% APPswe mutant (APPswe displayed alterations morphology distribution. Specifically, mitochondria exhibited fragmented structure an abnormal distribution accumulating around perinuclear area. These changes were abolished by treatment with β-site APP-cleaving enzyme inhibitor IV. From functional perspective, overexpression affected at multiple levels, including elevating reactive oxygen species decreasing membrane potential, reducing ATP production, also caused neuronal such as differentiation deficiency upon retinoic acid treatment. At molecular level, levels dynamin-like 1 OPA1 significantly decreased whereas Fis1 increased APPwt cells. Notably, these rescued deficiency, failed to rescue fragmentation parameters, restore normal Overexpression or Aβ-derived diffusible ligand led reduced coverage processes differentiated primary hippocampal Based data, concluded APP, through causes imbalance fission/fusion results distribution, which contributes dysfunction.

Язык: Английский

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Oxidative Stress and the Pathogenesis of Alzheimer's Disease

Oxidative Medicine and Cellular Longevity, Год журнала: 2013, Номер 2013, С. 1 - 10

Опубликована: Янв. 1, 2013

Alzheimer's disease (AD) is the most common neurodegenerative that causes dementia in elderly. Patients with AD suffer a gradual deterioration of memory and other cognitive functions, which eventually leads to complete incapacity death. A complicated array molecular events has been implicated pathogenesis AD. The major pathological characteristics brains are presence senile plaques, neurofibrillary tangles, neuronal loss. Growing evidence demonstrated oxidative stress an important factor contributing initiation progression However, mechanisms lead disruption redox balance sources free radicals remain elusive. excessive reactive oxygen species may be generated from such as mitochondria dysfunction and/or aberrant accumulation transition metals, while abnormal Abeta tau proteins appears promote imbalance. resulted Abeta- or tau-induced neurotoxicity. In addition, suggested augment production aggregation facilitate phosphorylation polymerization tau, thus forming vicious cycle promotes

Язык: Английский

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Oxidative stress in Alzheimer’s disease

Neuroscience Bulletin, Год журнала: 2014, Номер 30(2), С. 271 - 281

Опубликована: Март 24, 2014

Язык: Английский

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Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases

BMC Medical Genomics, Год журнала: 2009, Номер 2(1)

Опубликована: Янв. 8, 2009

The production of peroxide and superoxide is an inevitable consequence aerobic metabolism, while these particular 'reactive oxygen species' (ROSs) can exhibit a number biological effects, they are not themselves excessively reactive thus especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species lead to the catalytic very dangerous hydroxyl radical, which exceptionally damaging, major cause chronic inflammation. We review considerable wide-ranging evidence for involvement this combination (su)peroxide in large indeed pathological processes inflammatory disorders, those involving progressive degradation cellular organismal performance. These diseases share great many similarities might be considered have common (i.e. iron-catalysed free radical generation). studies reviewed include focused on series cardiovascular, metabolic neurological diseases, where found sites plaques lesions, as well showing significance aging longevity. effective chelation by natural or synthetic ligands (and potentially therapeutic) importance. As systems properties, we need recognise that observables multiple molecular causes, studying them isolation leads inconsistent patterns apparent causality when it simultaneous factors responsible. This explains, instance, decidedly mixed effects antioxidants been observed, since some circumstances (especially presence iron) molecules nominally actually act pro-oxidants. reduction redox stress requires suitable levels both chelators. Some polyphenolic may serve roles. Understanding exact speciation liganding all its states crucial separating various pro- anti-inflammatory activities. Redox stress, innate immunity anti-)inflammatory cytokines linked via signalling pathways NF-kappaB p38, oxidative roles here seemingly involved upstream IkappaB kinase (IKK) reaction. In cases possible identify mechanisms ROSs synergistically autocatalytically, leading 'runaway' hard control unless one tackles action simultaneously. such statins erythropoietin, traditionally associated activity, do 'pleiotropic' benefit here. Overall argue, synthesising widely dispersed literature, role has rather underappreciated past, activity underpins behaviour degrade over time. integrative, systems-level approach novel therapeutic targets.

Язык: Английский

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100 Years and Counting: Prospects for Defeating Alzheimer's Disease

Science, Год журнала: 2006, Номер 314(5800), С. 781 - 784

Опубликована: Ноя. 3, 2006

This week marks a century since the first description of Alzheimer's disease (AD). Despite approval several drugs for AD, continues to rob millions their memories and lives. Fortunately, many new therapies directly targeting mechanisms underlying AD are now in pipeline. Among investigative clinical trials strategies block pathogenic amyloid-β peptides rescue vulnerable neurons from degeneration. Complementary but less mature aim prevent copathogenic effects apolipoprotein E microtubule-associated protein tau. New insights into selective neuronal vulnerability link between aging may provide additional entry points therapeutic interventions. The predicted increase cases over next few decades makes development better treatments matter utmost importance urgency.

Язык: Английский

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Alzheimer Disease

Disease-a-Month, Год журнала: 2010, Номер 56(9), С. 484 - 546

Опубликована: Сен. 1, 2010

Язык: Английский

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Predictors of maintaining cognitive function in older adults

Neurology, Год журнала: 2009, Номер 72(23), С. 2029 - 2035

Опубликована: Июнь 8, 2009

Background: Although several risk factors for cognitive decline have been identified, much less is known about that predict maintenance of function in advanced age. Methods: We studied 2,509 well-functioning black and white elders enrolled a prospective study. Cognitive was measured using the Modified Mini-Mental State Examination at baseline years 3, 5, 8. Random effects models were used to classify participants as maintainers (cognitive change slope ≥0), minor decliners (slope <0 >1 SD below mean), or major ≤1 mean). Logistic regression identify domain-specific associated with being maintainer vs decliner. Results: Over 8 years, 30% maintained function, 53% showed decline, 16% had decline. In multivariate model, variables significantly decliner age (odds ratio [OR] = 0.65, 95% confidence interval [CI] 0.55–0.77 per 5 years), race (OR 1.72, CI 1.30–2.28), high school education level greater 2.75, 1.78–4.26), ninth grade literacy 4.85, 3.00–7.87), weekly moderate/vigorous exercise 1.31, 1.06–1.62), not smoking 1.84, 1.14–2.97). Variables compared are reported. Conclusion: Elders who maintain unique profile differentiates them from those Importantly, some these modifiable thus may be implemented prevention programs promote successful aging. Further, differ which impact treatment strategies.

Язык: Английский

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