Lancet neurology
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Apolipoprotein E (APOE) is a 299-aminoacid protein encoded by the APOE gene. Three common polymorphisms in the APOE gene, ɛ2, ɛ3, and ɛ4, result in a single aminoacid change in the APOE protein. APOE ɛ2, ɛ3, and ɛ4 alleles strongly alter, in a dose-dependent manner, the likelihood of developing Alzheimer's disease and cerebral amyloid angiopathy. ⋯ Because convincing evidence ties the APOE genotype to risk of Alzheimer's disease and cerebral amyloid angiopathy, APOE has been studied in other neurological diseases. APOE ɛ4 is associated with poor outcome after traumatic brain injury and brain haemorrhage, although the mechanisms underlying these associations are unclear. The possibility that APOE has a role in these and other neurological diseases has been of great interest, but convincing associations have not yet emerged.
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Review
The sirtuin pathway in ageing and Alzheimer disease: mechanistic and therapeutic considerations.
Advances in gerontology have yielded crucial insights into the molecular and biochemical aspects of the ageing process. The sirtuin pathway, which is most notable for its association with the anti-ageing effects of calorie restriction, has received particular attention, and pharmacological or transgenic upregulation of the sirtuin pathway has shown promising results in laboratory models of ageing. Alzheimer's disease is a neurodegenerative disease that is imposing an increasing burden on society, and is the leading cause of senile dementia worldwide. The lack of therapies for Alzheimer's disease provides a strong incentive for the development of an effective treatment strategy and, interestingly, research has uncovered a mechanism of action of the sirtuin pathway that might have therapeutic potential for Alzheimer's disease. ⋯ SIRT1, one of the seven mammalian proteins of the sirtuin family of NAD(+)-dependent deacetylases, has recently been shown to attenuate amyloidogenic processing of amyloid-β protein precursor (APP) in cell culture studies in vitro and in transgenic mouse models of Alzheimer's disease. Mechanistically, SIRT1 increases α-secretase production and activity through activation of the α-secretase gene ADAM10. Because α-secretase is the enzyme responsible for the non-amyloidogenic cleavage of APP, upregulation of α-secretase shifts APP processing to reduce the pathological accumulation of the presumptive toxic Aβ species that results from β-secretase and γ-secretase activity. Interestingly, the spatial patterns of Aβ deposition in the brain might correlate with increased aerobic glycolysis in those regions. Because aerobic glycolysis depletes cellular levels of NAD(+) (through a decreased NAD(+)/NADH ratio), it is possible that a corresponding downregulation of the NAD(+)-dependent sirtuin pathway contributes to the amyloidogenic processing of APP. WHERE NEXT?: The specific inhibition of Aβ generation by SIRT1 coupled with the potential link between aerobic glycolysis, NAD(+) depletion, and amyloidogenesis through the sirtuin pathway has translational implications. On the one hand, the possible underlying role of the sirtuin pathway in Alzheimer's disease onset and development might increase our understanding of this devastating condition. On the other hand, therapeutic upregulation of SIRT1 might provide opportunities for the amelioration of Alzheimer's-disease-type neuropathology through inhibition of amyloidogenesis. Ultimately, further analysis into both aspects is necessary if any progress is to be made.
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Some patients with early-onset Alzheimer's disease (AD) present with a distinct phenotype. Typically, the first and most salient characteristic of AD is episodic memory impairment. A few patients, however, present with focal cortical, non-memory symptoms, such as difficulties with language, visuospatial, or executive functions. ⋯ Additionally, theAPOE ɛ4 genotype seems to predispose patients to vulnerability in the medial temporal areas, which leads to memory loss. Conversely, patients negative for the APOE ɛ4 allele and with early-onset AD are more likely to be predisposed to vulnerability of cerebral networks beyond the medial temporal lobes. Other factors are probably involved in determining the pattern of atrophy, but these are currently unknown.
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Randomized Controlled Trial Multicenter Study Comparative Study
Preladenant in patients with Parkinson's disease and motor fluctuations: a phase 2, double-blind, randomised trial.
Preladenant is an adenosine 2A (A₂(A)) receptor antagonist. In animal models of Parkinson's disease, preladenant monotherapy improves motor function without causing dyskinesia and, as an adjunct to levodopa, it improves motor function without worsening dyskinesia. We aimed to assess the efficacy and safety of preladenant in patients with Parkinson's disease and motor fluctuations who were receiving levodopa and other antiparkinsonian drugs. ⋯ Schering-Plough, a subsidiary of Merck.
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Comparative Study
α-Synuclein and tau concentrations in cerebrospinal fluid of patients presenting with parkinsonism: a cohort study.
Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy are brain disorders characterised by intracellular α-synuclein deposits. We aimed to assess whether reduction of α-synuclein concentrations in CSF was a marker for α-synuclein deposition in the brain, and therefore diagnostic of synucleinopathies. ⋯ American Parkinson Disease Association, Stifterverband für die Deutsche Wissenschaft, Michael J Fox Foundation for Parkinson's Research, National Institutes of Health, Parkinson Research Consortium Ottawa, and the Government of Canada.