Neurobiology of aging
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Neurobiology of aging · May 2014
Improving the knowledge of amyotrophic lateral sclerosis genetics: novel SOD1 and FUS variants.
Amyotrophic lateral sclerosis (ALS) is as an adult-onset neurodegenerative disorder involving both upper and lower motor neurons. About 5% of all cases exhibit signs of frontotemporal degeneration (FTD). We established the mutation frequency of C9ORF72, SOD1, TARDBP, and FUS genes in 307 patients with sporadic ALS, 46 patients with familial ALS (FALS), and 73 patients affected with FTD, all originating from the northeastern part of Italy. ⋯ Interestingly, the single base deletion on FUS was observed in an homozygous state, suggesting a recessive pattern of inheritance. No point mutations were identified on FTD cohort. Although useful to direct genetic testing, this study results expand the current knowledge of ALS genetics.
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Neurobiology of aging · May 2014
Neuropep-1 ameliorates learning and memory deficits in an Alzheimer's disease mouse model, increases brain-derived neurotrophic factor expression in the brain, and causes reduction of amyloid beta plaques.
Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid beta (Aβ) deposits, hyperphosphorylated tau deposition, and cognitive dysfunction. Abnormalities in the expression of brain-derived neurotrophic factor (BDNF), which plays an important role in learning and memory formation, have been reported in the brains of AD patients. A BDNF modulating peptide (Neuropep-1) was previously identified by positional-scanning synthetic peptide combinatorial library. ⋯ Furthermore, we found that Neuropep-1-injected 3xTg-AD mice exhibit dramatically reduced Aβ plaque deposition and Aβ levels without affecting tau pathology. Neuropep-1 treatment does not alter the expression or activity of full-length amyloid precursor protein, α-, β-, or γ-secretase, but levels of insulin degrading enzyme, an Aβ degrading enzyme, were increased. These findings suggest Neuropep-1 may be a therapeutic candidate for the treatment of AD.
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Neurobiology of aging · Apr 2014
Triggering receptor expressed on myeloid cells 2 variant is rare in late-onset Alzheimer's disease in Han Chinese individuals.
Recent studies have reported that a rare mutation of triggering receptor expressed on myeloid cells 2 gene (TREM2 [rs75932628-T]) has significantly increased the risk of late-onset Alzhemier's disease (LOAD) in European-descendent population. To date, no study has investigated the association between rare mutations of TREM2 and LOAD risk in non-European population. ⋯ Most importantly, the previously reported rare variants in European-descendent population including rs75932628-T (predicted to cause an R47H substitution) were absent in our cohort. These findings suggest that mutations in exon2 of TREM2 were unlikely to play a key role in the susceptibility of LOAD in the northern Han Chinese population.
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Neurobiology of aging · Apr 2014
Disentangling the effects of age and APOE on neuropathology and late life cognitive decline.
Age and APOE are the most robust risk factors for dementia and cognitive decline, but the underlying neurobiology remains unclear. We examined the extent to which the hallmark pathologies of Alzheimer's disease, Lewy body disease, and cerebrovascular diseases account for the association of age and APOE with decline in episodic memory versus nonepisodic cognitive abilities. Up to 20 waves of longitudinal cognitive data were collected from 858 autopsied participants in 2 ongoing clinical-pathologic cohort studies of aging. ⋯ The effect of age on decline in episodic memory was mediated by Aβ, mesial temporal and neocortical tau tangles, and macroscopic infarcts; age on decline in nonepisodic cognition was mediated by Aβ, neocortical tangles, and macroscopic infarcts. The effect of APOE on decline in episodic memory was mediated by Aβ, mesial temporal and neocortical tangles, and neocortical Lewy bodies; APOE on nonepisodic cognition was mediated by Aβ, neocortical tangles, and neocortical Lewy bodies. There were no direct effects of age and APOE on decline after accounting for these pathologic pathways.
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A causative association was recently demonstrated between homozygous TREM2 mutations and frontotemporal dementia (FTD)-like syndrome and between heterozygous TREM2 exon2 genetic variations and late-onset Alzheimer's disease (AD). The objective of this study was to evaluate whether heterozygous TREM2 genetic variations might be associated to the risk of FTD. TREM2 exon 2 was sequenced in a group of 1030 subjects-namely, 352 patients fulfilling clinical criteria for FTD, 484 healthy control subjects (HCs), and 194 patients with AD. ⋯ The FTD and AD groups were not significantly different with regard to TREM2 genetic variation frequency (AD: 2.6%, p = 0.39). Heterozygous TREM2 mutations modulate the risk of FTD in addition to increasing susceptibility to AD. Additional studies are warranted to investigate the possible role of these mutations in the pathogenesis of neurodegenerative disorders.