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1.  Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer’s disease patients 
Neurobiology of aging  2013;34(9):2091-2099.
Epigenetic dysregulation of gene expression is thought to be critically involved in the pathophysiology of Alzheimer’s disease (AD). Recent studies indicate that DNA methylation and DNA hydroxymethylation are 2 important epigenetic mechanisms that regulate gene expression in the aging brain. However, very little is known about the levels of markers of DNA methylation and hydroxymethylation in the brains of patients with AD, the cell-type specificity of putative AD-related alterations in these markers, as well as the link between epigenetic alterations and the gross pathology of AD. The present quantitative immunohistochemical study investigated the levels of the 2 most important markers of DNA methylation and hydroxymethylation, that is, 5-methylcytidine (5-mC) and 5-hydroxymethylcytidine (5-hmC), in the hippocampus of AD patients (n = 10) and compared these to non demented, age-matched controls (n = 10). In addition, the levels of 5-hmC in the hippocampus of a pair of monozygotic twins discordant for AD were assessed. The levels of 5-mC and 5-hmC were furthermore analyzed in a cell-type and hippocampal subregion–specific manner, and were correlated with amyloid plaque load and neurofibrillary tangle load. The results showed robust decreases in the hippocampal levels of 5-mC and 5-hmC in AD patients (19.6% and 20.2%, respectively). Similar results were obtained for the twin with AD when compared to the non-demented co-twin. Moreover, levels of 5-mC as well as the levels of 5-hmC showed a significant negative correlation with amyloid plaque load in the hippocampus (rp = −0.539, p = 0.021 for 5-mC and rp = −0.558, p = 0.016 for 5-hmC). These human postmortem results thus strengthen the notion that AD is associated with alterations in DNA methylation and hydroxymethylation, and provide a basis for further epigenetic studies identifying the exact genetic loci with aberrant epigenetic signatures.
doi:10.1016/j.neurobiolaging.2013.02.021
PMCID: PMC3955118  PMID: 23582657
Alzheimer’s disease; Epigenetics; DNA methylation; DNA hydroxymethylation; Amyloid
2.  Carvedilol as a potential novel agent for the treatment of Alzheimer’s disease 
Neurobiology of aging  2010;32(12):2321.e1-2321.e12.
Oligomeric β-amyloid (Aβ) has recently been linked to synaptic plasticity deficits, which play a major role in progressive cognitive decline in Alzheimer’s disease (AD). Here we present evidence that chronic oral administration of carvedilol, a nonselective β-adrenergic receptor blocker, significantly attenuates brain oligomeric Aβ content and cognitive deterioration in two independent AD mouse models. We found that carvedilol treatment significantly improved neuronal transmission, and that this improvement was associated with the maintenance of number of the less stable “learning” thin spines in the brains of AD mice. Our novel observation that carvedilol interferes with the neuropathologic, biochemical and electrophysiological mechanisms underlying cognitive deterioration in AD supports the potential development of carvedilol as a treatment for AD.
doi:10.1016/j.neurobiolaging.2010.05.004
PMCID: PMC2966505  PMID: 20579773
Oligomeric Aβ; cognitive function; spatial memory; basal neuronal transmission; dendritic spine; synaptic plasticity; bioavailability
3.  Protein kinase C activity is associated with prefrontal cortical decline in aging 
Neurobiology of aging  2007;30(5):782-792.
Aging is associated with deficiencies in the prefrontal cortex, including working memory impairment, and compromised integrity of neuronal dendrites. Although protein kinase C (PKC) is implicated in structural plasticity, and overactivation of PKC results in working memory impairments in young animals, the role of PKC in prefrontal cortical impairments in the aged has not been examined. This study provides the first evidence that PKC activity is associated with prefrontal cortical dysfunction in aging. Pharmacological inhibition of PKC with chelerythrine rescued working memory impairments in aged rats and enhanced working memory in aged rhesus monkeys. Improvement correlated with age, with older monkeys demonstrating a greater degree of improvement following PKC inhibition. Furthermore, PKC activity within the prefrontal cortex was inversely correlated with the length of basal dendrites of prefrontal cortical neurons, as well as with working memory performance in aged rats. Together these findings indicate that PKC is dysregulated in aged animals and that PKC inhibitors may be useful in the treatment of cognitive deficits in the elderly.
doi:10.1016/j.neurobiolaging.2007.08.020
PMCID: PMC2711775  PMID: 17919783
prefrontal cortex; aging; working memory; protein kinase C; dendritic spines; chelerythrine; dendrites
4.  Stereologic estimates of total spinophilin-immunoreactive spine number in area 9 and the CA1 field: relationship with the progression of Alzheimer’s disease 
Neurobiology of aging  2007;29(9):1296-1307.
The loss of presynaptic markers is thought to represent a strong pathologic correlate of cognitive decline in Alzheimer’s disease (AD). Spinophilin is a postsynaptic marker mainly located to the heads of dendritic spines. We assessed total numbers of spinophilin-immunoreactive puncta in the CA1 and CA3 fields of hippocampus and area 9 in 18 elderly individuals with various degrees of cognitive decline. The decrease in spinophilin-immunoreactivity was significantly related to both Braak neurofibrillary tangle (NFT) staging and clinical severity but not Aβ deposition staging. The total number of spinophilin-immunoreactive puncta in CA1 field and area 9 were significantly related to MMSE scores and predicted 23.5% and 61.9% of its variability. The relationship between total number of spinophilin-immunoreactive puncta in CA1 field and MMSE scores did not persist when adjusting for Braak NFT staging. In contrast, the total number of spinophilin-immunoreactive puncta in area 9 was still significantly related to the cognitive outcome explaining an extra 9.6% of MMSE and 25.6% of the Clinical Dementia Rating scores variability. Our data suggest that neocortical dendritic spine loss is an independent parameter to consider in AD clinicopathologic correlations.
doi:10.1016/j.neurobiolaging.2007.03.007
PMCID: PMC2569870  PMID: 17420070
Alzheimer’s disease; cognition; synapses; tangles

Results 1-4 (4)