Interleukins, Inflammation, and Mechanisms of Alzheimer's Disease

Weisman, David; Hakimian, Edwin; Ho, Gilbert

doi:10.1016/s0083-6729(06)74020-1

Cited by 82 publications

(65 citation statements)

References 121 publications

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“…In AD brain the activation of the microglia is triggered by oligomeric amyloid beta peptide and amyloid fibrils and the resulting pro-inflammatory response mediated by IL-1, IL-6 and TNF-α, complement system, chemokines etc. plays an important role in neurodegeneration of AD, while anti-inflammatory cytokines IL-4, IL-10 and TGF-β also liberated from the microglia may assist in neuroprotection [40,148,150,151,152]. The role of pro-inflammatory cytokines in AD pathogenesis has recently gained some intense attention because of the evidence suggesting the activation of the inflammosome, NLRP3, in the brain of transgenic AD mice and patients of mild cognitive impairment and AD dementia [153,154].…”

Section: Proinflammatory Cytokinesmentioning

confidence: 99%

Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment

Chakrabarti¹,

Khemka²,

Banerjee³

et al. 2015

Aging and disease

105

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Alzheimer's disease (AD), the major cause of dementia among the elderly world-wide, manifests in familial and sporadic forms, and the latter variety accounts for the majority of the patients affected by this disease. The etiopathogenesis of sporadic AD is complex and uncertain. The autopsy studies of AD brain have provided limited understanding of the antemortem pathogenesis of the disease. Experimental AD research with transgenic animal or various cell based models has so far failed to explain the complex and varied spectrum of AD dementia. The review, therefore, emphasizes the importance of AD related risk factors, especially those with metabolic implications, identified from various epidemiological studies, in providing clues to the pathogenesis of this complex disorder. Several metabolic risk factors of AD like hypercholesterolemia, hyperhomocysteinemia and type 2 diabetes have been studied extensively both in epidemiology and experimental research, while much less is known about the role of adipokines, proinflammatory cytokines and vitamin D in this context. Moreover, the results from many of these studies have shown a degree of variability which has hindered our understanding of the role of AD related risk factors in the disease progression. The review also encompasses the recent recommendations regarding clinical and neuropathological diagnosis of AD and brings out the inherent uncertainty and ambiguity in this area which may have a distinct impact on the outcome of various population-based studies on AD-related risk factors.

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Section: Proinflammatory Cytokinesmentioning

confidence: 99%

Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment

Chakrabarti¹,

Khemka²,

Banerjee³

et al. 2015

Aging and disease

105

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“…This concept, though still controversial, is supported by the fact that the level of soluble Aβ correlates better with dementia than does plaque burden in AD patients [101,102]. In aqueous solutions, Aβ undergoes a time-and concentrationdependent transition from a soluble α-helical to an insoluble β-sheet structure.…”

Section: Cotinine-inhibited Aβ 1-42 Aggregationmentioning

confidence: 99%

Cotinine: A Potential New Therapeutic Agent against Alzheimer's disease

Echeverrı́a

Zeitlin

2012

CNS Neuroscience & Therapeutics

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SUMMARYTobacco smoking has been correlated with a lower incidence of Alzheimer's disease (AD). This negative correlation has been attributed to nicotine's properties. However, the undesired side-effects of nicotine and the absence of clear evidence of positive effects of this drug on the cognitive abilities of AD patients have decreased the enthusiasm for its therapeutic use. In this review, we discuss evidence showing that cotinine, the main metabolite of nicotine, has many of the beneficial effects but none of the negative side-effects of its precursor. Cotinine has been shown to be neuroprotective, to improve memory in primates as well as to prevent memory loss, and to lower amyloid-beta (Aβ)) burden in AD mice. In AD, cotinine's positive effect on memory is associated with the inhibition of Aβ aggregation, the stimulation of pro-survival factors such as Akt, and the inhibition of pro-apoptotic factors such as glycogen synthase kinase 3 beta (GSK3β). Because stimulation of the α7 nicotinic acetylcholine receptors (α7nAChRs) positively modulates these factors and memory, the involvement of these receptors in cotinine's effects are discussed. Because of its beneficial effects on brain function, good safety profile, and nonaddictive properties, cotinine may represent a new therapeutic agent against AD. Alzheimer's disease: The Cholinergic System as a Therapeutic TargetAlzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia [1,2]. The disease is characterized by extracellular accumulation of senile plaques, mainly composed of aggregated forms of the amyloid-beta peptide (Aβ), as well as intracellular accumulation of neurofibrillary tangles of the microtubule-associated protein tau [1]. These neuropathological changes are associated with structural brain abnormalities, inflammation, and cognitive impairment such as impairment of working memory in AD patients. The progressive loss of memory in AD patients correlates with increased levels of Aβ and the deterioration of the cholinergic system in the brain. The degenerative process involves a sequence of pathological events, including early degeneration of the cerebral basal forebrain and subsequent deterioration of the cortical cholinergic system [3,4]. This deterioration commonly includes a reduction in the levels of acetylcholine (ACh) and α3, α4, and α7 nicotinic ACh receptors (nAChRs) as well as a decrease in the activity of choline acetyltranferase in the brain [5].Of these nAChRs, the α7 receptors are considered to be ideal therapeutic targets for several neurological conditions, including AD, schizophrenia, and Parkinson's disease (PD) as well as tobacco addiction [6,7]. The α7nAChR is a homomeric pentamer that has a high permeability to calcium (P Ca :P Na ≈ 10), and undergoes rapid and reversible desensitization and pronounced inward rectification [8]. The α7 subunit is highly expressed in the cortex, hippocampus, and hypothalamus [8], and has also been suggested to have functionally important expression in ...

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“…These two insoluble protein aggregates accumulate in susceptible regions of the brain and are accompanied by a chronic inflammatory response and extensive oxidative damage (Sastre et al 2006;Weisman et al 2006;Fuller et al 2010). …”

Section: Histopathology Of Alzheimer's Disease -Key To Pathogenesis Amentioning

confidence: 99%

Induced pluripotent stem cells as tools for disease modelling and drug discovery in Alzheimer’s disease

et al. 2012

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The use of induced pluripotent stem cells (iPSCs), whereby a patient's somatic cells can be reprogrammed to a pluripotent state by the forced expression of a defined set of transcription factors, has the potential to enable in vitro disease modelling and be used for drug discovery programs. Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder that leads to a decline in memory and cognition. Fibroblasts were taken from AD patients (or non‐AD controls) and cultured under specific conditions to generate iPSCs which were then provided with growth factors to allow differentiation into neurons. While AD‐iPSCs were morphologically indistinguishable from control‐iPSCs, differentiated cells showed differing responses to both cellular stresses and neuroprotective drugs. Since these cells are derived from individual patients, the use of iPSCs has provided novel insights into disease pathogenesis, providing information on an individual's variations in the disease process and their cellular response to drugs.

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Interleukins, Inflammation, and Mechanisms of Alzheimer's Disease

Cited by 82 publications

References 121 publications

Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment

Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment

Cotinine: A Potential New Therapeutic Agent against Alzheimer's disease

Induced pluripotent stem cells as tools for disease modelling and drug discovery in Alzheimer’s disease

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