Neurobiology of aging
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Neurobiology of aging · Oct 2014
PERK mediates eIF2α phosphorylation responsible for BACE1 elevation, CREB dysfunction and neurodegeneration in a mouse model of Alzheimer's disease.
Emerging evidence suggests that aberrant phosphorylation of eukaryotic initiation factor-2α (eIF2α) may induce synaptic failure and neurodegeneration through persistent translational inhibition of global protein synthesis. However, elevated phospho-eIF2α also paradoxically causes translational activation of a subset of messenger RNAs such as the β-secretase enzyme, β-site APP-cleaving enzyme 1 (BACE1) and cAMP response element binding protein (CREB) repressor, activating transcription factor 4 (ATF4). Therefore, we tested whether genetic reduction of the eIF2α kinase PERK may prevent these deleterious events and mitigate Alzheimer's disease (AD)-like neuropathology and cognitive impairments in the 5XFAD mouse model. ⋯ Notably, PERK haploinsufficiency also prevented BACE1 elevations, resulting in reduced levels of amyloid-β peptides and plaque burden in 5XFAD mice. Moreover, CREB dysfunction was restored in PERK(+/-)·5XFAD mice concomitant with reversal of ATF4 upregulation. Together, these findings suggest that PERK may be a disease-modifying therapeutic target to prevent multiple memory-disrupting mechanisms associated with AD.
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Neurobiology of aging · Oct 2014
Case ReportsHomozygous TREM2 mutation in a family with atypical frontotemporal dementia.
TREM2 mutations were first identified in Nasu-Hakola disease, a rare autosomal recessive disease characterized by recurrent fractures because of bone cysts and presenile dementia. Recently, homozygous and compound heterozygous TREM2 mutations were identified in rare families with frontotemporal lobar degeneration (FTLD) but without bone involvement. We identified a p. ⋯ This study further demonstrates the implication of TREM2 mutations in FTLD phenotypes. It illustrates the variability of bone phenotype and underlines the frequency of atypical signs in TREM2 carriers. This and previous studies evidence that TREM2 mutation screening should be limited to autosomal recessive FTLD with atypical phenotypes characterized by: (1) a very young age at onset (20-50 years); (2) early parietal and hippocampal deficits; (3) the presence of seizures and parkinsonism; (4) suggestive extensive white matter lesions and corpus callosum thickness on brain magnetic resonance imaging.
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Neurobiology of aging · Sep 2014
Rescue of cognitive-aging by administration of a neurogenic and/or neurotrophic compound.
Aging is characterized by a progressive decline of cognitive performance, which has been partially attributed to structural and functional alterations of hippocampus. Importantly, aging is the major risk factor for the development of neurodegenerative diseases, especially Alzheimer's disease. An important therapeutic approach to counteract the age-associated memory dysfunctions is to maintain an appropriate microenvironment for successful neurogenesis and synaptic plasticity. ⋯ In vivo magnetic resonance spectroscopy revealed age-dependent alterations in hippocampal content of several metabolites. Remarkably, P021 was effective in significantly reducing myoinositol (INS) concentration, which was increased in aged compared with young rats. These findings suggest that stimulating endogenous neuroprotective mechanisms is a potential therapeutic approach to cognitive aging, Alzheimer's disease, and associated neurodegenerative disorders and P021 is a promising compound for this purpose.
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Neurobiology of aging · Sep 2014
Distinct pattern of hypometabolism and atrophy in preclinical and predementia Alzheimer's disease.
The goal of the present study was to determine the earliest patterns of hypometabolism and atrophy in the development of Alzheimer's disease (AD). Stages of AD were defined by positron emission tomography imaging evidence of cortical amyloid pathology in addition to cognitive criteria. ⋯ Region of interest- and voxel-based analyses showed significant hypometabolism but not atrophy in CN Aβ+ subjects compared with CN Aβ- subjects. The results suggest that hypometabolism exceeds atrophy in preclinical AD, supporting the notion that amyloid load may affect synaptic activity, leading to synaptic loss and subsequent neuronal loss.
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Neurobiology of aging · Sep 2014
Hippocampal subfield volumes at 7T in early Alzheimer's disease and normal aging.
We compared hippocampal subfield and entorhinal cortex (ERC) volumes between patients with mild cognitive impairment (MCI), Alzheimer's disease (AD), and controls without cognitive impairment. Additionally, we investigated the relation between age and hippocampal subfields and ERC in controls. We performed ultra-high field 0.7 mm(3) 7Tesla magnetic resonance imaging in 16 patients with amnestic MCI, 9 with AD, and 29 controls. ⋯ Older age was significantly associated with smaller CA1 and DG&CA4 volumes. In conclusion, almost all hippocampal subfields and ERC show volume reductions in patients with AD compared with controls and patients with MCI. Future, larger studies should determine which subfields are affected earliest in the disease process and what mechanisms underlie the volume loss.