-
[show abstract]
[hide abstract]
ABSTRACT: Histamine H(3) receptor antagonists have been proposed as a novel therapeutic approach for the symptomatic treatment of Alzheimer's disease (AD). However, it is unclear whether there is a neurochemical basis for extending their potential use in vascular and mixed dementias. In this study, we measured cortical H(3) receptors in patients with subcortical ischemic vascular dementia (SIVD) and mixed SIVD/AD (MIX).
Radioligand binding assays using [(3)H]GSK189254 were used to measure H(3) receptors in the postmortem frontal cortex, anterior cingulate gyrus and hippocampus of a cohort of longitudinally assessed SIVD, MIX and age-matched controls.
H(3) receptor levels were unchanged in SIVD and MIX in all areas studied. Furthermore, frontal H(3) receptor densities negatively correlated with predeath assessment of cognition using Mini-Mental State Examination (MMSE) scores.
Our data suggest that H(3) receptors are preserved in SIVD and MIX, thus supporting further assessments of H(3) antagonists as potential therapeutics in these dementias.
Journal of the neurological sciences 11/2011; 315(1-2):110-4. · 2.32 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Glutamatergic AMPA receptors are of clinical significance in dementia because of their roles in mediating fast excitatory neurotransmission and other synaptic events relevant to cognition. Reductions in the AMPA receptor GluR2 subunit are well-established in Alzheimer's disease (AD), but the status of GluR2 in subcortical ischemic vascular dementia (SIVD) and mixed AD/SIVD (MIX) has not been investigated. In this study we measured GluR2 immunoreactivity and mRNA levels in the postmortem neocortex of a longitudinally assessed cohort of SIVD and MIX, together with age-matched controls. We found that GluR2 immunoreactivity and mRNA were up-regulated in SIVD, but remained unchanged in MIX. Furthermore, higher GluR2 immunoreactivity was associated with milder cognitive impairment and lower concentrations of Aβ42 peptide and phosphorylated tau. Our study suggests that GluR2 up-regulation may be an adaptive process in SIVD, and that this process is repressed in the presence of concomitant AD in mixed dementia.
Neurochemistry International 03/2011; · 2.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Previous studies have shown extensive serotonergic deficits in the hippocampus of Alzheimer's disease (AD) patients. However, it is unclear whether such deficits play a role in non-cognitive, neuropsychiatric behaviors that occur frequently in AD and cause significant caregiver distress.
In this study, we aimed to correlate serotonergic markers in the AD hippocampus with neuropsychiatric behaviors.
Using postmortem hippocampal homogenates from aged controls as well as a cohort of longitudinally assessed AD patients, measurements of 5-HT(1A) receptors, 5-HT(2A) receptors, and serotonin re-uptake (5-HTT) sites were performed by binding with (3)H-labeled 8-OH-DPAT, ketanserin, and citalopram, respectively.
Alterations of 5-HT(1A) receptors and 5-HTT were found to be differentially involved in neuropsychiatric behaviors, with loss of 5-HT(1A) receptors specifically correlated with depressive symptoms, while 5-HTT sites were preserved or up-regulated in patients with aggressive behaviors.
Our data suggest that neuropsychiatric behaviors in AD share certain neurochemical features with psychiatric disorders like major depression and that serotonergic drugs used in psychiatric disorders may also be efficacious against behavioral symptoms in AD.
Psychopharmacologia 02/2011; 213(2-3):431-9. · 4.08 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The cannabinoid CB1 receptor has gained much attention as a potential pharmacotherapeutic target in various neurodegenerative diseases including Alzheimer's disease (AD). However, the relation of CB1 receptors to cognitive function in AD is at present unclear. In this study, postmortem brain tissues from a cohort of prospectively assessed, neuropathologically confirmed AD patients and aged controls were used to measure CB1 receptors by immunoblotting, and a subset of subjects also had [(3)H]SR141716A binding. Correlational analyses were then performed for the neurochemical and cognitive data. We found that CB1 receptor levels in were unchanged AD in the brain regions assessed (frontal cortex, anterior cingulate gyrus, hippocampus, caudate nucleus). Within the AD group, frontal cortical CB1 immunoreactivity correlated with cognitive scores assessed within a year of death. Our study suggests that CB1 receptors are intact in AD and may play a role in preserving cognitive function. Therefore, CB1 receptors should be further assessed as a potential therapeutic target in AD.
Neurochemistry International 10/2010; 57(8):985-9. · 2.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Neuropsychiatric behaviours occur frequently in Alzheimer's disease and other dementias and are thought to arise from the neurodegenerative process. However, it is unclear whether neurodegenerative changes in the hippocampus are associated with neuropsychiatric behaviours such as aggression. In this study, semiquantitative measurements of cell loss, atrophy, neuritic plaque and neurofibrillary tangle load in the postmortem hippocampus were taken for dementia patients, prospectively assessed for neuropsychiatric behaviours. It was found that increased tangle load, but not other hippocampal neuropathological variables, was associated with increased severity of aggressive behaviours and presence of chronic aggression. This study suggests a pathogenic link between neurofibrillary tangle load and aggressive behaviours in the hippocampus of dementia patients.
Neuroreport 09/2010; 21(17):1111-5. · 1.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We studied the hypothesis that disturbances in 5-HT_{6} receptor function in the temporal cortex may contribute to clinical symptoms of Alzheimer's disease (AD). 5-HT_{6} density and 5-HT levels were significantly decreased in a cohort of AD patients prospectively assessed for cognitive/behavioral symptoms. cAMP formation after stimulation with the selective 5-HT_{6} receptor agonist E-6801 was significantly lower (p<0.01) in AD (170.02 +/- 27.53 pmol/mg prot.) compared to controls (823.33 +/-196.67). In addition, the ratio cAMP formation after stimulation with E-6801/5-HT_{6} receptor density was significantly lower (p< 0.01) in AD (6.67 +/- 0.83) compared to controls (16.67 +/- 3.33). Splitting these results by sex, 5-HT_{6} receptor activation was significantly lower (p< 0.01) in AD females compared to males (121.67 +/- 30.02 vs. 231.67 +/- 34.17 pmol/mg prot). 5-HT_{6} density and 5-HT levels were significantly correlated (p < or = 0.01) in both controls and AD patients, although in AD, this correlation was lost in females. Psychosis factor was the best predictor of reduced 5-HT levels or adenylate cyclase activity after E-6801 stimulation, the former result being due to females. It may be suggested that psychotic symptoms may be related to a dysregulation of 5-HT_{6} activation by 5-HT in the temporal cortex. These results are discussed in terms of purported influence of sex and therapeutical approaches to psychosis in AD.
Journal of Alzheimer's disease: JAD 05/2008; 14(1):43-50. · 3.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: There are few studies on the clinical and neurochemical correlates of postsynaptic cholinergic dysfunction in Alzheimer's disease (AD). We have previously found that attenuation of guanine nucleotide-binding (G-) protein coupling to muscarinic M(1) receptors in the neocortex was associated with dementia severity. The present study aims to study whether this loss of M(1)/G-protein coupling is related to alterations in signaling kinases and NMDA receptors. Postmortem frontal cortices of 22 AD subjects and 12 elderly controls were obtained to measure M(1) receptors, M(1)/G-protein coupling, NMDA receptors as well as protein kinase C (PKC) and Src kinase activities. We found that the extent of M(1)/G-protein coupling loss was correlated with reductions in PKC activity and NMDA receptor density. In contrast, Src kinase activity was neither altered nor associated with M(1)/G-protein coupling. Given the well established roles of neuronal PKC signaling and NMDA receptor function in cognitive processes, our results lend further insight into the mechanisms by which postsynaptic cholinergic dysfunction may underlie the cognitive features of AD, and suggest alternative therapeutic targets to cholinergic replacement.
Neurobiology of aging 10/2007; 28(9):1381-7. · 5.94 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Glutamatergic deficits are established neuropathological features of Alzheimer's disease (AD) and are known to correlate with cognitive impairments. In contrast, the role of glutamatergic alterations in behavioral and psychological symptoms of dementia (BPSD) is unclear. There is considerable preclinical evidence for the importance of glycine recognition sites (GlyRS) of N-methyl-D-aspartate (NMDA) receptors in the regulation of anxiety behaviors. This study aimed to correlate several glutamatergic measures with chronic anxiety in AD. Twenty-one AD patients assessed by the Neuropsychiatric Inventory (NPI) were divided into low anxiety (LA) and high anxiety (HA) subgroups. GlyRS and NMDA channel were measured by brain homogenate binding with [(3)H]MDL105,519 and [(3)H]MK-801, respectively. Densities of NMDA receptor NR2A, NR2B and alternate spliced NR1 subunits were quantified by immunoblotting. We found that the binding affinity to GlyRS was significantly higher in HA compared to LA, and this higher GlyRS affinity correlated with selective reduction of NR2A density as well as with elevated anxiety scores. Our observations suggest a novel mechanism whereby subunit specific changes in the NMDA receptor complex may be linked to chronic anxiety in AD via effects on GlyRS function. We propose that NR2A and GlyRS should be further assessed as novel targets of behavioral pharmacotherapy in AD.
Neurobiology of aging 05/2007; 29(10):1524-32. · 5.94 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Impaired transmission of acetylcholine-mediated signaling by postsynaptic muscarinic M1 receptors has been postulated to underlie the limited efficacy of cholinergic replacement therapies in Alzheimer's disease (AD). However, a clear relationship between the functionality of M1 receptors and dementia severity has not been demonstrated. The present study aims to measure M1 coupling to its nucleotide binding (G-) protein in the AD neocortex, and to correlate neurochemical findings with clinical features. A cohort of dementia patients was longitudinally assessed for cognitive decline, with postmortem neuropathological confirmation of AD diagnosis. Measures of M1 receptor density, M1/G-protein coupling and choline acetyltransferase (ChAT) activities were performed in the frontal and temporal cortex of 24 AD patients as well as in 12 age-matched controls. We found that M1 receptor densities were unchanged in AD, which contrasted with significantly reduced M1 coupling to G-proteins in severely demented AD patients. Loss of M1/G-protein coupling in the frontal cortex, but not the temporal cortex, also correlated with the rate of cognitive decline. Additionally, correlations between M1/G-protein coupling and ChAT activities were demonstrated in both regions. These results suggest that defective coupling of neocortical M1 receptors to G-proteins is a neurochemical substrate of cognitive decline in AD. Based on its associations with ChAT deficits and dementia severity, we propose that M1/G-protein uncoupling may have a significant role in the disease mechanism of AD and thus may be considered to be a potential therapeutic target.
Neurobiology of aging 10/2006; 27(9):1216-23. · 5.94 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The effects of the APOE epsilon4 allele on a range of pre- and postsynaptic cholinergic markers were studied in a cohort of community-based Alzheimer's disease (AD) patients. Compared with age-matched controls, the postmortem AD neocortex showed decreased choline acetyltransferase (ChAT) and acetyl cholinesterase activities, lower muscarinic M2, and nicotinic alpha4beta2 receptor densities, as well as reduced M1 receptor coupling to G-proteins. However, the epsilon4 allele was dose-dependently correlated only with higher losses of ChAT activities. AD patients with two epsilon4 alleles also had more beta-amyloid containing senile plaques in the temporal cortex compared to patients with 0/1 epsilon4. This study suggests that APOE epsilon4 selectively affects presynaptic cholinergic function which may contribute to the clinical and neuropathological features of AD.
Neurobiology of Disease 07/2006; 22(3):555-61. · 5.40 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Densities of serotonin transporters (5-HTT) in the postmortem neocortex of behaviorally assessed Alzheimer's disease (AD) patients and aged controls were measured by radioligand binding with [3H]citalopram. It was found that 5-HTT sites in the temporal cortex of AD patients with prominent antemortem anxiety were unaltered compared with controls, but were reduced in non-anxious AD subjects. Furthermore, homozygosity for the high activity allele of a functional polymorphism in the 5-HTT gene promoter region (5-HTTLPR) was associated with both increased [3H]citalopram binding and occurrence of anxiety in the AD subjects. Since serotonin-synthesizing neurons are known to be lost in the AD cortex, this study suggests that the preservation of 5-HTT may exacerbate serotonergic deficits and underlie anxiety symptoms in AD.
Neuroreport 08/2003; 14(10):1297-300. · 1.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Previous studies have implicated brain serotonin 5-HT(1A) receptors in several CNS functions, including cognition, mood and emotional states. In Alzheimer disease (AD), cognitive impairment and behavioral symptoms are the main clinical features. However, the biochemical basis of such changes is poorly understood. Results from recent in vivo studies suggest that 5-HT(1A) receptors may be related to aggressive traits in healthy subjects. The present study investigated the state of 5-HT(1A) receptors in the postmortem neocortex of 33 AD patients prospectively assessed for cognition and behavioral symptoms, together with 20 matched controls, by saturation [(3)H]8-OH-DPAT binding assays. 5-HT(1A) receptor binding affinity (K(D)) and density (B(max)) were unchanged in the overall AD group compared with controls. Within the AD group, 5-HT(1A) receptor B(max) in the temporal cortex inversely correlated with aggression and dementia severity. However, multiple regression analyses showed that 5-HT(1A) receptor B(max) remained the best predictor for aggression, while temporal cortical neurofibrillary tangle grading was the best predictor for dementia severity. This suggests that 5-HT(1A) receptor alteration is directly related to aggression in AD, while dementia severity is more strongly related to the neurodegenerative process. Our data indicate further study of 5-HT(1A) receptors as a pharmacological target for the treatment of behavioral symptoms in AD.
Brain Research 07/2003; 974(1-2):82-7. · 2.73 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Serotonin1A receptor density and serotonin concentration were measured in the postmortem neocortex of 17 AD patients who had been prospectively assessed every four months with the Mini-Mental State Examination (MMSE) for a mean of 2.6 years till death. In the frontal cortex, serotonin levels correlated negatively with the annual rate of MMSE decline, while serotonin1A receptor density was positively correlated with the rate of MMSE decline. Our study suggests that reduced serotonin levels and increased serotonin1A receptor density are markers for accelerated cognitive decline in AD, and provides support for the use of serotonin1A antagonists in the treatment of AD.
Neuroreport 08/2002; 13(9):1175-8. · 1.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The effects of the APOE ε4 allele on a range of pre- and postsynaptic cholinergic markers were studied in a cohort of community-based Alzheimer's disease (AD) patients. Compared with age-matched controls, the postmortem AD neocortex showed decreased choline acetyltransferase (ChAT) and acetyl cholinesterase activities, lower muscarinic M2, and nicotinic α4β2 receptor densities, as well as reduced M1 receptor coupling to G-proteins. However, the ε4 allele was dose-dependently correlated only with higher losses of ChAT activities. AD patients with two ε4 alleles also had more β-amyloid containing senile plaques in the temporal cortex compared to patients with 0/1 ε4. This study suggests that APOE ε4 selectively affects presynaptic cholinergic function which may contribute to the clinical and neuropathological features of AD.
Neurobiology of Disease.
-
[show abstract]
[hide abstract]
ABSTRACT: Previous studies have implicated brain serotonin 5-HT1A receptors in several CNS functions, including cognition, mood and emotional states. In Alzheimer disease (AD), cognitive impairment and behavioral symptoms are the main clinical features. However, the biochemical basis of such changes is poorly understood. Results from recent in vivo studies suggest that 5-HT1A receptors may be related to aggressive traits in healthy subjects. The present study investigated the state of 5-HT1A receptors in the postmortem neocortex of 33 AD patients prospectively assessed for cognition and behavioral symptoms, together with 20 matched controls, by saturation [3H]8-OH-DPAT binding assays. 5-HT1A receptor binding affinity (KD) and density (Bmax) were unchanged in the overall AD group compared with controls. Within the AD group, 5-HT1A receptor Bmax in the temporal cortex inversely correlated with aggression and dementia severity. However, multiple regression analyses showed that 5-HT1A receptor Bmax remained the best predictor for aggression, while temporal cortical neurofibrillary tangle grading was the best predictor for dementia severity. This suggests that 5-HT1A receptor alteration is directly related to aggression in AD, while dementia severity is more strongly related to the neurodegenerative process. Our data indicate further study of 5-HT1A receptors as a pharmacological target for the treatment of behavioral symptoms in AD.
Brain Research.
