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1.  Cerebral β-amyloid deposition predicts HIV-associated neurocognitive disorders in APOE ε4 carriers 
AIDS (London, England)  2012;26(18):2327-2335.
Objective
The apolipoprotein E (APOE) ε4 allele enhances cerebral accumulation of β-amyloid (Aβ) and is a major risk factor for sporadic Alzheimer’s disease (AD). We hypothesized that HIV-associated neurocognitive disorders (HAND) would be associated with the APOE ε4 genotype and cerebral Aβ deposition.
Design
Clinico-pathological study of HIV-infected adults from four prospective cohorts in the U.S. National NeuroAIDS Tissue Consortium.
Methods
We used multivariable logistic regressions to model outcomes (Aβ plaques [immunohistochemistry] and HAND [standard criteria]) on predictors (APOE ε4 [allelic discrimination assay], older age [≥ 50 years], Aβ plaques, and their two-way interactions) and co-morbid factors.
Results
Isocortical Aβ deposits generally occurred as diffuse plaques and mild to moderate amyloid angiopathy. Isocortical phospho-Tau-immunoreactive neurofibrillary lesions were sparse. The APOE ε4 and older age were independently associated with the presence of Aβ plaques (adjusted odds ratio [OR] 10.16 and 5.77 [95% confidence interval (CI) 2.89–35.76 and 1.91–17.48], P=0.0003 and 0.0019, respectively, n=96). The probability of HAND was increased in the presence of Aβ plaques among APOE ε4 carriers (adjusted OR 30.00 [95% CI 1.41–638.63], P=0.029, n=15), but not in non-ε4 carriers (n=57).
Conclusion
The APOE ε4 and older age increased the likelihood of cerebral Aβ plaque deposition in HIV-infected adults. Generally Aβ plaques in HIV brains were immunohistologically different from those in symptomatic AD brains. Nonetheless, Aβ plaques were associated with HAND among APOE ε4 carriers. The detection of APOE ε4 genotype and cerebral Aβ deposition biomarkers may be useful in identifying living HAND subjects who could benefit from Aβ-targeted therapies.
doi:10.1097/QAD.0b013e32835a117c
PMCID: PMC3576852  PMID: 23018443
Apolipoprotein E; β-amyloid; HIV dementia; neurofibrillary pathology; phospho-Tau
2.  Antioxidant Sestrin-2 Redistribution to Neuronal Soma in Human Immunodeficiency Virus-Associated Neurocognitive Disorders 
Sestrin-2 is involved in p53-dependent antioxidant defenses and in the maintenance of metabolic homeostasis. We hypothesize that sestrin-2 expression is altered in the brains of subjects diagnosed with human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) due to neuronal oxidative stress. We studied sestrin-2 immunoreactivity in 42 isocortex sections from HIV-1-infected subjects compared to 18 age-matched non-HIV controls and 19 advanced Alzheimer's disease (AD) cases. With HIV infection, the sestrin-2 immunoreactivity pattern shifted from neuropil predominance (N) to neuropil and neuronal-soma co-dominance (NS) and neuronalsoma predominance (S; P < 0.0001, Chi-square test for linear trend). Among HIV cases showing the NS or S pattern, HAND cases were preferentially associated with the S pattern (n = 10 of 20) compared to cognitively intact cases (n = 1 of 11; P = 0.047, Fisher's exact test). In AD brains, sestrin-2 immunoreactivity was mostly intense in the neuropil and co-localized with phospho-Tau immunoreactivity in a subset of neurofibrillary lesions. Phospho-Tau-immunoreactive neurofibrillary lesions were rare in HIV cases and their occurrence was not associated with HAND. Levels of isocortical 8-hydroxy-deoxyguanosine (marker of nucleic acid oxidation) immunoreactivity were not significantly altered in HAND cases compared to cognitively intact HIV cases. In conclusion, the sestrin-2 immunoreactivity redistribution to neuronal soma in HAND suggests unique involvement of sestrin-2 in the pathophysiology of HAND, which is different from the role of sestrin-2 in AD pathogenesis. Alternatively, the difference in sestrin-2 immunoreactivity distribution between HAND and AD may be related to different degrees of severity or stages of oxidative stress.
doi:10.1007/s11481-012-9357-0
PMCID: PMC3573843  PMID: 22450766
Alzheimer's disease; HIV dementia; Neurofibrillary pathology; Oxidative stress; SESN2
3.  Increased cortical expression of FK506 binding protein-51 in HIV-associated neurocognitive disorders 
Journal of Neurovirology  2012;18(4):313-322.
FK506 binding protein (FKBP)-51 and FKBP52 act as molecular chaperones to control glucocorticoid receptor (GR) sensitivity. Dysregulation of proteins involved in GR-mediated signaling can lead to maladaptive stress response and aging-related cognitive decline. As HIV infection is related to chronic stress, we hypothesized that altered cortical expression of these proteins was associated with HIV-associated neurocognitive disorders (HAND). We used quantitative immunohistochemistry to assess expression levels of these proteins in the mid-frontal gyrus of 55 HIV-infected subjects free of cerebral opportunistic diseases compared to 20 age-matched non-HIV controls. The immunoreactivity normalized to the neuroanatomic area measured (IRn) for FKBP51 was increased in HIV subjects both in the cortex and subcortical white matter (p<0.0001, U test), while no significant alterations were observed for GR or FKBP52. Notably, the cortical FKBP51 IRn was higher in HAND subjects than in cognitively normal HIV subjects (p=0.02, U test). There was also a trend for increasing cortical FKBP51 IRn with the increasing severity of HAND (p=0.08, Kruskal-Wallis test). No significant changes in FKBP51 IRn were found with respect to hepatitis C virus infection, lifetime methamphetamine use, or antiretroviral treatment in HIV subjects. In conclusion, the increased cortical expression of FKBP51 (an inhibitor for GR activity) might represent negative feedback in an attempt to reduce GR sensitivity in the setting of chronic stress-induced elevation of GR-mediated signaling inherent in HIV infection. The further increased FKBP51 expression might lead to maladaptive stress response and HAND.
doi:10.1007/s13365-011-0076-8
PMCID: PMC3374917  PMID: 22234543
FKBP4; FKBP5; HIV dementia; Immunophilin; NR3C1
4.  Tyrosine kinase B protein expression is reduced in the cerebellum of patients with bipolar disorder 
Journal of affective disorders  2011;133(3):646-654.
Background
The role of the cerebellum in coordinating mental activity is supported by its connections with cerebral regions involved in cognitive/affective functioning, with decreased activities on functional neuroimaging observed in the cerebellum of schizophrenia patients performing mental tasks. Brain-derived neurotrophic factor (BDNF)-induced activation of tyrosine kinase B (TrkB) is essential to synaptic plasticity. We hypothesized that alterations in BDNF and TrkB expression in the cerebellum were associated with schizophrenia and affective disorders.
Methods
We employed immunohistochemistry and immunoblotting to quantify protein expression of BDNF and TrkB in the cerebellum of patients with schizophrenia, bipolar disorder, and major depression compared to controls (n=15 each).
Results
While TrkB immunoreactivity in each of the molecular and granule-cell layers was reduced in all 3 disease groups (12–34%) compared to the control (P=0.018 and 0.038, respectively, ANOVA), only the reduction in bipolar disorder remained statistically significant upon Tukey-Kramer post hoc analyses (P=0.019 and 0.021, respectively). Apparent decreases in BDNF immunoreactivity in all 3 disease groups (12–30%) compared to the control were not statistically significant. TrkB immunoreactivity was not significantly associated with any of the demographic, clinical, and postmortem variables. Immunoblotting displayed an 85-kDa TrkB-immunoreactive band, consistent with a truncated isoform, in all 60 cases.
Limitations
On immunoblotting, apparent decreases in 85-kDa-TrkB levels in all 3 disease groups compared to the control were not statistically significant.
Conclusions
Our finding of reduced TrkB expression in bipolar disorder suggests that dysregulation of TrkB-mediated neurotrophin signaling in the cerebellum may play a role in the pathophysiology of this disease.
doi:10.1016/j.jad.2011.04.044
PMCID: PMC3163025  PMID: 21612826
Bipolar disorder; Brain-derived neurotrophic factor; Cerebellum; Major depression; Schizophrenia; TrkB
5.  System-Wide Immunohistochemical Analysis of Protein Co-Localization 
PLoS ONE  2012;7(2):e32043.
Background
The analysis of co-localized protein expression in a tissue section is often conducted with immunofluorescence histochemical staining which is typically visualized in localized regions. On the other hand, chromogenic immunohistochemical staining, in general, is not suitable for the detection of protein co-localization. Here, we developed a new protocol, based on chromogenic immunohistochemical stain, for system-wide detection of protein co-localization and differential expression.
Methodology/Principal Findings
In combination with a removable chromogenic stain, an efficient antibody stripping method was developed to enable sequential immunostaining with different primary antibodies regardless of antibody's host species. Sections were scanned after each staining, and the images were superimposed together for the detection of protein co-localization and differential expression. As a proof of principle, differential expression and co-localization of glutamic acid decarboxylase67 (GAD67) and parvalbumin proteins was examined in mouse cortex.
Conclusions/Significance
All parvalbumin-containing neurons express GAD67 protein, and GAD67-positive neurons that do not express parvalbumin were readily visualized from thousands of other neurons across mouse cortex. The method provided a global view of protein co-localization as well as differential expression across an entire tissue section. Repeated use of the same section could combine assessments of co-localization and differential expression of multiple proteins.
doi:10.1371/journal.pone.0032043
PMCID: PMC3283725  PMID: 22363794
6.  High-definition characterization of cerebral β-amyloid angiopathy in Alzheimer's disease 
Human pathology  2010;41(11):1601-1608.
The occurrence and progression of cerebral β-amyloid angiopathy (CAA) and β-amyloid plaques in sporadic Alzheimer's disease may be attributed to aging-related deficiencies in β-amyloid drainage along cerebral perivascular pathways. To elucidate high-definition characteristics of cerebral β-amyloid deposition, we performed immunogold silver staining for β-amyloid-40 and β-amyloid-42 on semithin LR White-embedded tissue sections from 7 Alzheimer's disease/severe CAA, 9 Alzheimer's disease/mild CAA, 5 old control and 4 young control autopsy brains. In vessel walls, β-amyloid-40 and β-amyloid-42 deposits were unevenly distributed along the adventitia and among the medial smooth muscle cells. β-Amyloid-40 immunoreactivity appeared greater than that of β-amyloid-42 in vessel walls, with β-amyloid-42 being preferentially located on their abluminal regions. In capillary walls, either β-amyloid-40 or β-amyloid-42 deposits or both were present in 6 of 7 severe CAA and 1 of 9 mild CAA cases, with a marked variation in thickness and focally abluminal excrescences. In 5 of 7 severe CAA cases, a subset of β-amyloid-laden capillaries revealed either β-amyloid-40 or β-amyloid-42 deposits or both radiating from their walls into the surrounding neuropil (“pericapillary deposits”). No vascular β-amyloid-40 or β-amyloid-42 deposits were observed in any of the controls. In conclusion, the patterns of β-amyloid-42 and β-amyloid-40 immunoreactivity in vessel walls suggest that β-amyloid deposits occur in the vascular basement membranes along cerebral perivascular drainage pathways, extending from cortical capillaries to leptomeningeal arteries. The presence of pericapillary β-amyloid deposits suggests that a subset of β-amyloid plaques originate from β-amyloid-laden capillaries, particularly in Alzheimer's disease brains that exhibit preferential capillary CAA involvement.
doi:10.1016/j.humpath.2010.04.011
PMCID: PMC2956850  PMID: 20688356
Cerebral amyloid angiopathy; LR White resin; Immunogold silver staining
7.  Cerebral Microinfarcts Associated with Severe Cerebral β-Amyloid Angiopathy 
Cerebral amyloid angiopathy (CAA) is common in elderly individuals, especially those affected with Alzheimer's disease. To investigate whether the presence of severe CAA (SCAA) in the brains of demented patients was associated with a higher burden of old microinfarcts than those with mild CAA (MCAA), 18 brains with SCAA were compared to 21 brains with MCAA. Immunohistochemistry for CD68 was employed to highlight old microinfarcts in tissue blocks from various brain regions. Old microinfarcts, manually counted by light microscopy, were present in 14 of 18 SCAA brains, and in 7 of 21 MCAA brains (P = 0.01, 2-tailed Fisher’s exact test). The average number of old microinfarcts across geographic regions in each brain ranged from 0 to 1.95 (mean rank 24.94, sum of ranks 449) in the SCAA group, and from 0 to 0.35 (mean rank 15.76, sum of ranks 331) in the MCAA group (P = 0.008, 2-tailed Mann-Whitney U test). Frequent old microinfarcts in demented individuals with severe CAA may contribute a vascular component to the cognitive impairment in these patients.
doi:10.1111/j.1750-3639.2009.00322.x
PMCID: PMC3127860  PMID: 19725828
cerebrovascular disease; dementia; multi-infarct dementia; vascular dementia
8.  Increased hippocampal accumulation of autophagosomes predicts short-term recognition memory impairment in aged mice 
Age  2011;34(2):305-316.
Constitutive macroautophagy involved in the turnover of defective long-lived proteins and organelles is crucial for neuronal homeostasis. We hypothesized that macroautophagic dysregulation in selective brain regions was associated with memory impairment in aged mice. We used the single-trial object recognition test to measure short-term memory in 18 aged mice compared to 22 young mice and employed immunohistochemistry to assess cellular distribution of proteins involved in the selective degradation of ubiquitinated proteins via macroautophagy. Values of the discrimination ratio (DR, a measure of short-term recognition memory performance) in aged mice were significantly lower than those in young mice (median, 0.54 vs. 0.67; p = 0.005, U test). Almost exclusively in aged mice, there were clusters of puncta immunoreactive for microtubule-associated protein 1 light chain 3 (LC3), ubiquitin- and LC3-binding protein p62, and ubiquitin in neuronal processes predominantly in the hippocampal formation, olfactory bulb/tubercle, and cerebellar cortex. The hippocampal burden of clustered puncta immunoreactive for LC3 and p62 exhibited inverse linear correlations with DR in aged mice (ρ = −0.48 and −0.55, p = 0.044 and 0.018, respectively, Spearman’s rank correlation). These findings suggest that increased accumulation of autophagosomes within neuronal processes in selective brain regions is characteristic of aging. The dysregulation of macroautophagy can adversely affect the turnover of aggregate-prone proteins and defective organelles, which may contribute to memory impairment in aged mice.
doi:10.1007/s11357-011-9234-4
PMCID: PMC3312638  PMID: 21431350
Autophagy; Brain aging; MAP1LC3; Object recognition test; p62; Ubiquitin
9.  Differential Expression of Immunophilins FKBP51 and FKBP52 in the Frontal Cortex of HIV-Infected Patients with Major Depressive Disorder 
Patients infected with human immunodeficiency virus (HIV) have a higher risk of developing major depressive disorder (MDD) than the general population. Immunophilins FKBP51 and FKBP52 are expressed in cortical neurons and regulate the function of the glucocorticoid receptor (GR). Previous reports have shown that genetic variants in the FKBP5 gene encoding FKBP51 are linked to psychiatric disorders. We sought to determine whether immunophilins are upregulated in HIV infection. To determine whether FKBP52 and FKBP51 are associated with MDD and/or HIV, we compared protein and gene expression in autopsy tissues from the frontal cortical gray matter. The study cases were divided into five groups: control, MDD, MDD with psychosis, HIV+, and HIV+ with MDD. Gene expression and protein levels were determined by real-time PCR and Western blot analysis of fresh frozen tissues. Genotyping of previously published alleles of the FKBP5 gene was also performed. We found correlation of upregulation of both immunophilins in the HIV-infected groups. In the HIV+ population with MDD, FKBP4 expression is significantly higher while FKBP5 is more variable. After analyzing the FKBP5 gene for single nucleotide polymorphisms, we found that rs3800373 CC genotype is more frequent in the MDD and MDD/Psychosis groups. We hypothesized that the levels of FKBP51, as modulator of the nuclear translocation of GR, would be lower in MDD. Instead, an increase in FKBP51 at both the transcript (FKBP5) and protein level correlated with MDD. Increased FKBP4 expression of correlated to HIV+MDD but not to HIV without MDD.
doi:10.1007/s11481-009-9146-6
PMCID: PMC2929573  PMID: 19199039
HIV; immunophilins; major depressive disorder; glucocorticoid receptor
10.  Short-term recognition memory impairment is associated with decreased expression of FK506 binding protein 51 in the aged mouse brain 
Age  2010;32(3):309-322.
Evidence suggests that increased glucocorticoid receptor (GR) signaling may contribute to cognitive decline with age. We hypothesized that alterations in GR signaling pathway molecules, FK506 binding protein (FKBP) 51 and FKBP52, were associated with memory impairment in aged mice. We used the single-trial object recognition test to measure short-term memory in 18 aged mice compared to 22 young mice, and employed quantitative immunohistochemistry to assess cellular expression of those three proteins in the frontal cortex, hippocampal CA1, and dentate gyrus. Values of the discrimination ratio (DR, a measure of novelty preference) in aged mice were significantly lower than those in young mice (mean 0.54 vs. 0.67, p = 0.003, t test). Aged mice with DR below 0.54 were considered impaired (n = 9). In the three neuroanatomic regions studied, the immunoreactivity normalized to the area measured (IRn) for GR was significantly increased in aged mice regardless of their task performance compared to young mice (p < 0.005), as was the FKBP52 IRn (p < 0.007, U test). In the frontal cortex and CA1, the FKBP51 IRn was significantly lower in impaired aged mice than in unimpaired aged mice (p < 0.01 and <0.05, respectively) and in young mice (p < 0.05 and <0.01, respectively, Dunn’s post hoc test). In aged mice, the frontal cortex FKBP51 IRn correlated directly with DR (rs = 0.68, p = 0.002, Spearman rank correlation). These observations suggest that recognition memory impairment in aged mice is associated with decreased FKBP51 expression that may promote GR-mediated glucocorticoid signaling to a greater extent than in unimpaired aged mice.
doi:10.1007/s11357-010-9145-9
PMCID: PMC2926850  PMID: 20422297
Aging; Brain immunophilins; FKBP51; FKBP52; Glucocorticoid receptor signaling; Object recognition test

Results 1-10 (10)