The tumor suppressor p53 is a key regulator of apoptosis and functions upstream in the apoptotic cascade by both indirectly and directly regulating Bcl-2 family proteins. In cells expressing ...wild-type (WT) p53, the HDM2 protein binds to p53 and blocks its activity. Inhibition of HDM2:p53 interaction activates p53 and causes apoptosis or cell-cycle arrest. Here, we investigated the ability of the novel HDM2 inhibitor CGM097 to potently and selectively kill WT p53-expressing AML cells. The antileukemic effects of CGM097 were studied using cell-based proliferation assays (human AML cell lines, primary AML patient cells, and normal bone marrow samples), apoptosis, and cell-cycle assays, ELISA, immunoblotting, and an AML patient-derived in vivo mouse model. CGM097 potently and selectively inhibited the proliferation of human AML cell lines and the majority of primary AML cells expressing WT p53, but not mutant p53, in a target-specific manner. Several patient samples that harbored mutant p53 were comparatively unresponsive to CGM097. Synergy was observed when CGM097 was combined with FLT3 inhibition against oncogenic FLT3-expressing cells cultured both in the absence as well as the presence of cytoprotective stromal-secreted cytokines, as well as when combined with MEK inhibition in cells with activated MAPK signaling. Finally, CGM097 was effective in reducing leukemia burden in vivo. These data suggest that CGM097 is a promising treatment for AML characterized as harboring WT p53 as a single agent, as well as in combination with other therapies targeting oncogene-activated pathways that drive AML.
Objective:
Sorting mechanisms that cause the amyloid precursor protein (APP) and the β‐secretases and γ‐secretases to colocalize in the same compartment play an important role in the regulation of Aβ ...production in Alzheimer's disease (AD). We and others have reported that genetic variants in the Sortilin‐related receptor (SORL1) increased the risk of AD, that SORL1 is involved in trafficking of APP, and that underexpression of SORL1 leads to overproduction of Aβ. Here we explored the role of one of its homologs, the sortilin‐related VPS10 domain containing receptor 1 (SORCS1), in AD.
Methods:
We analyzed the genetic associations between AD and 16 SORCS1–single nucleotide polymorphisms (SNPs) in 6 independent data sets (2,809 cases and 3,482 controls). In addition, we compared SorCS1 expression levels of affected and unaffected brain regions in AD and control brains in microarray gene expression and real‐time polymerase chain reaction (RT‐PCR) sets, explored the effects of significant SORCS1‐SNPs on SorCS1 brain expression levels, and explored the effect of suppression and overexpression of the common SorCS1 isoforms on APP processing and Aβ generation.
Results:
Inherited variants in SORCS1 were associated with AD in all datasets (0.001 < p
< 0.049). In addition, SorCS1 influenced APP processing. While overexpression of SorCS1 reduced γ‐secretase activity and Aβ levels, the suppression of SorCS1 increased γ‐secretase processing of APP and the levels of Aβ.
Interpretations:
These data suggest that inherited or acquired changes in SORCS1 expression or function may play a role in the pathogenesis of AD. Ann Neurol 2011;69:47–64.
Introduction
This study examined plasma glial fibrillary acidic protein (GFAP) as a biomarker of cognitive impairment due to Alzheimer's disease (AD) with and against plasma neurofilament light chain ...(NfL), and phosphorylated tau (p‐tau)181+231.
Methods
Plasma samples were analyzed using Simoa platform for 567 participants spanning the AD continuum. Cognitive diagnosis, neuropsychological testing, and dementia severity were examined for cross‐sectional and longitudinal outcomes.
Results
Plasma GFAP discriminated AD dementia from normal cognition (adjusted mean difference = 0.90 standard deviation SD) and mild cognitive impairment (adjusted mean difference = 0.72 SD), and demonstrated superior discrimination compared to alternative plasma biomarkers. Higher GFAP was associated with worse dementia severity and worse performance on 11 of 12 neuropsychological tests. Longitudinally, GFAP predicted decline in memory, but did not predict conversion to mild cognitive impairment or dementia.
Discussion
Plasma GFAP was associated with clinical outcomes related to suspected AD and could be of assistance in a plasma biomarker panel to detect in vivo AD.
The goal of this study was to examine the clinical presentation of chronic traumatic encephalopathy (CTE) in neuropathologically confirmed cases.
Thirty-six adult male subjects were selected from all ...cases of neuropathologically confirmed CTE at the Boston University Center for the Study of Traumatic Encephalopathy brain bank. Subjects were all athletes, had no comorbid neurodegenerative or motor neuron disease, and had next-of-kin informants to provide retrospective reports of the subjects' histories and clinical presentations. These interviews were conducted blind to the subjects' neuropathologic findings.
A triad of cognitive, behavioral, and mood impairments was common overall, with cognitive deficits reported for almost all subjects. Three subjects were asymptomatic at the time of death. Consistent with earlier case reports of boxers, 2 relatively distinct clinical presentations emerged, with one group whose initial features developed at a younger age and involved behavioral and/or mood disturbance (n = 22), and another group whose initial presentation developed at an older age and involved cognitive impairment (n = 11).
This suggests there are 2 major clinical presentations of CTE, one a behavior/mood variant and the other a cognitive variant.
We examined baseline and longitudinal associations between plasma neurofilament light (NfL) and total tau (t-tau), and the clinical presentation of Alzheimer's disease (AD). A total of 579 ...participants (238, normal cognition NC; 185, mild cognitive impairment MCI; 156, AD dementia) had baseline blood draws; 82% had follow-up evaluations. Plasma samples were analyzed for NfL and t-tau using Simoa technology. Baseline plasma NfL was higher in AD dementia than MCI (standardized mean difference = 0.55, 95% CI: 0.37–0.73) and NC (standardized mean difference = 0.68, 95% CI: 0.49–0.88), corresponded to Clinical Dementia Rating scores (OR = 1.94, 95% CI: 1.35–2.79), and correlated with all neuropsychological tests (r's = 0.13–0.42). Longitudinally, NfL did not predict diagnostic conversion but predicted decline on 3/10 neuropsychological tests. Baseline plasma t-tau was higher in AD dementia than NC with a small effect (standardized mean difference = 0.33, 95% CI: 0.10–0.57) but not MCI. t-tau did not statistically significant predict any longitudinal outcomes. Plasma NfL may be useful for the detection of AD dementia and monitoring of disease progression. In contrast, there was minimal evidence in support of plasma t-tau.
•Baseline plasma neurofilament light was higher in Alzheimer's disease dementia than mild cognitive impairment and normal cognition.•Baseline plasma neurofilament light was associated with baseline cognitive test score and predicted subsequent decline but did not predict diagnostic conversion.•Baseline plasma total tau was higher in Alzheimer's disease dementia than mild cognitive impairment and normal cognition.•There were no statistically significant effects for baseline plasma total tau on cognitive decline or diagnostic conversion.
Background
Alzheimer’s disease (AD) is characterized by cognitive deterioration and extracellular amyloid beta deposits and neurofibrillary tangles in the brain. These may occur in tandem with ...markers of Lewy body (LB) and vascular dementia (VaD). Studying bulk and single‐cell expression profiles for these disorders may identify factors shared between and unique to AD and other dementias.
Method
Bulk RNA‐sequencing was performed using 210 human postmortem hippocampal region samples obtained from brains donated to the BU Alzheimer Disease Research Center. After quality checks (QC), 191 samples classified as AD+LB (n=43), AD+VaD (n=54), AD alone (n=73), and controls (n=17) were included in the study. Analysis of expression differences between each of these AD groups and controls was performed using limma software with models including covariates for age, sex, RNA quality, plate, and two surrogate variables to adjust for unknown variation. Weighted gene co‐expression network analysis (WGCNA) was used to identify clusters of co‐expressed genes. Additionally, high quality single‐nuclei RNA sequencing data (snRNA‐seq) was obtained from 8 of the 210 hippocampal samples with an average of 6000 cells detected per sample and 1800 genes per cell after QC. This snRNA‐seq data was integrated with the bulk data using Scissor to identify cell populations positively and negatively associated with AD.
Result
481 genes were differentially expressed between AD cases and controls. Upregulated genes in AD subjects were enriched for cilia function and morphological development and downregulated genes in AD subjects were enriched for mitochondrial energy production. A WGCNA module strongly associated with ciliary function was found to be overrepresented in AD (and especially AD+VaD) samples compared to controls. Multiple brain cell types were detected from our snRNA‐seq data. Of these, a subpopulation of ependymal cells related to the ciliary WGCNA module was positively associated with AD status.
Conclusion
Our results suggest that different sets of co‐expressed genes in hippocampus distinguish AD brains with and without pathological hallmarks related to other forms of dementia, and brains without AD pathology. This study also provides preliminary evidence for the involvement of ependymal cell populations in AD
Plasma-to-autopsy studies are essential for validation of blood biomarkers and understanding their relation to Alzheimer’s disease (AD) pathology. Few such studies have been done on phosphorylated ...tau (p-tau) and those that exist have made limited or no comparison of the different p-tau variants. This study is the first to use immunoprecipitation mass spectrometry (IP-MS) to compare the accuracy of eight different plasma tau species in predicting autopsy-confirmed AD. The sample included 123 participants (AD = 69, non-AD = 54) from the Boston University Alzheimer’s disease Research Center who had an available ante-mortem plasma sample and donated their brain. Plasma samples proximate to death were analyzed by targeted IP-MS for six different tryptic phosphorylated (p-tau-181, 199, 202, 205, 217, 231), and two non-phosphorylated tau (195–205, 212–221) peptides. NIA-Reagan Institute criteria were used for the neuropathological diagnosis of AD. Binary logistic regressions tested the association between each plasma peptide and autopsy-confirmed AD status. Area under the receiver operating curve (AUC) statistics were generated using predicted probabilities from the logistic regression models. Odds Ratio (OR) was used to study associations between the different plasma tau species and CERAD and Braak classifications. All tau species were increased in AD compared to non-AD, but p-tau217, p-tau205 and p-tau231 showed the highest fold-changes. Plasma p-tau217 (AUC = 89.8), p-tau231 (AUC = 83.4), and p-tau205 (AUC = 81.3) all had excellent accuracy in discriminating AD from non-AD brain donors, even among those with CDR < 1). Furthermore, p-tau217, p-tau205 and p-tau231 showed the highest ORs with both CERAD (OR
p-tau217
= 15.29, OR
p-tau205
= 5.05 and OR
p-tau231
= 3.86) and Braak staging (OR
p-tau217
= 14.29, OR
p-tau205
= 5.27 and OR
p-tau231
= 4.02) but presented increased levels at different amyloid and tau stages determined by neuropathological examination. Our findings support plasma p-tau217 as the most promising p-tau species for detecting AD brain pathology. Plasma p-tau231 and p-tau205 may additionally function as markers for different stages of the disease.
Background
Plasma‐to‐autopsy studies are essential for validation of plasma biomarkers for the detection of Alzheimer’s disease (AD). Few such studies have been done and those that exist have had ...limited or no comparison of the different tau epitopes. This plasma‐to‐autopsy study is the first to use immunoprecipitation mass spectrometry (IP‐MS) to compare the accuracy of eight different plasma tau epitopes (six p‐tau, two total tau) in predicting autopsy‐confirmed AD.
Method
The sample included 123 participants from the Boston University Alzheimer’s Disease Research Center who had an available antemortem plasma sample and donated their brain for neuropathological examination. Plasma samples proximate to death were analyzed for six different plasma p‐tau (181+199+202+205+217+231) and two total tau (t‐tau) epitopes (195‐205, 212‐221) simultaneously using IP‐MS. NIA‐Reagan Institute criteria were used for the neuropathological diagnosis of AD. Binary logistic regressions tested the association between each plasma epitope and autopsy‐confirmed AD status. Area under the receiver operating curve (AUC) statistics were generated using predicted probabilities from the logistic regression models. Analyses were repeated stratified by Clinical Dementia Rating (CDR) score (i.e., <1 and ≥1) at the time of blood draw. Odds Ratio (OR) was used to study associations between the different plasma tau species and CERAD and Braak classifications.
Result
Table 1 shows sample characteristics. Sixty‐nine of the 123 (56.1%) brain donors had autopsy‐confirmed AD and the average interval between blood draw and death was ∼5 years. Table 2 summarizes logistic regressions and Figure 1 displays ROC curves. Plasma p‐tau217 (AUC = 89.8), p‐tau231 (AUC = 83.4), and p‐tau205 (AUC = 81.3) all had excellent accuracy in discriminating AD from non‐AD brain donors. Among those with CDR≥1, p‐tau217, p‐tau231, and p‐tau205 had outstanding discrimination and all other epitopes had excellent discrimination. Among those with CDR<1, p‐tau217 (AUC = 86.3) and p‐tau231 (AUC = 80.6) still had excellent discrimination accuracy; p‐tau181, p‐tau205, and t‐tau195‐209 had acceptable discrimination. Furthermore, p‐tau217, p‐tau205 and p‐tau231 were the tau species that showed higher ORs with both CERAD (ORp‐tau217 = 15.29, ORp‐tau205 = 5.05 and ORp‐tau231 = 3.86) and Braak staging (ORp‐tau217 = 14.29, ORp‐tau205 = 5.27 and ORp‐tau231 = 4.02).
Conclusion
Plasma levels of p‐tau217, p‐tau231, and p‐tau205 showed the best discrimination accuracy for AD confirmed neuropathology in both mild and severe cognitive impairment.
Traumatic encephalopathy syndrome (TES) is defined as the clinical manifestation of the neuropathological entity chronic traumatic encephalopathy (CTE). A core feature of TES is neurobehavioral ...dysregulation (NBD), a neuropsychiatric syndrome in repetitive head impact (RHI)-exposed individuals, characterized by a poor regulation of emotions/behavior. To discover biological correlates for NBD, we investigated the association between biomarkers of inflammation (interleukin (IL)-1β, IL-6, IL-8, IL-10, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) in cerebrospinal fluid (CSF) and NBD symptoms in former American football players and unexposed individuals.
Our cohort consisted of former American football players, with (n = 104) or without (n = 76) NBD diagnosis, as well as asymptomatic unexposed individuals (n = 55) from the DIAGNOSE CTE Research Project. Specific measures for NBD were derived (i.e., explosivity, emotional dyscontrol, impulsivity, affective lability, and a total NBD score) from a factor analysis of multiple self-report neuropsychiatric measures. Analyses of covariance tested differences in biomarker concentrations between the three groups. Within former football players, multivariable linear regression models assessed relationships among log-transformed inflammatory biomarkers, proxies for RHI exposure (total years of football, cumulative head impact index), and NBD factor scores, adjusted for relevant confounding variables. Sensitivity analyses tested (1) differences in age subgroups (< 60, ≥ 60 years); (2) whether associations could be identified with plasma inflammatory biomarkers; (3) associations between neurodegeneration and NBD, using plasma neurofilament light (NfL) chain protein; and (4) associations between biomarkers and cognitive performance to explore broader clinical symptoms related to TES.
CSF IL-6 was higher in former American football players with NBD diagnosis compared to players without NBD. Furthermore, elevated levels of CSF IL-6 were significantly associated with higher emotional dyscontrol, affective lability, impulsivity, and total NBD scores. In older football players, plasma NfL was associated with higher emotional dyscontrol and impulsivity, but also with worse executive function and processing speed. Proxies for RHI exposure were not significantly associated with biomarker concentrations.
Specific NBD symptoms in former American football players may result from multiple factors, including neuroinflammation and neurodegeneration. Future studies need to unravel the exact link between NBD and RHI exposure, including the role of other pathophysiological pathways.
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