Higher CSF sTREM2 and microglia activation associate with slower rate of beta-amyloid accumulation
Ontology highlight
ABSTRACT:
SUBMITTER: Prof. Michael Ewers
PROVIDER: S-SCDT-EMM-2020-12308 | biostudies-other |
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Microglia activation is the brain's major immune response to amyloid plaques in Alzheimer's disease (AD). Both cerebrospinal fluid (CSF) levels of soluble TREM2 (sTREM2), a biomarker of microglia activation, and microglia PET are increased in AD; however, whether an increase in these biomarkers is associated with reduced amyloid-beta (Aβ) accumulation remains unclear. To address this question, we pursued a two-pronged translational approach. Firstly, in non-demented and demented individuals, we tested CSF sTREM2 at baseline to predict (i) amyloid PET changes over ∼2 years and (ii) tau PET cross-sectionally assessed in a subset of patients. We found higher CSF sTREM2 associated with attenuated amyloid PET increase and lower tau PET. Secondly, in the AppNL-G-F mouse model of amyloidosis, we studied baseline 18 F-GE180 microglia PET and longitudinal amyloid PET to test the microglia vs. Aβ association, without any confounding co-pathologies often present in AD patients. Higher microglia PET at age 5 months was associated with a slower amyloid PET increase between ages 5-to-10 months. In conclusion, higher microglia activation as determined by CSF sTREM2 or microglia PET shows protective effects on subsequent amyloid accumulation.
| S-EPMC7507349 | biostudies-literature
Project description:IntroductionThe extracellular deposition of β-amyloid (Aβ) is a pathological hallmark in Alzheimer's disease (AD), which induces microglial activation in the pathology of AD. The expression of serine/threonine-protein kinase 2 (SRPK2) is increased in the brain tissues of patients with AD. In this study, we examined the effect of SRPK2 in the activation of microglia.MethodsMicroglia (BV2) cells were cultured and the expression of SRPK2 was enhanced by transfection of SRPK2 recombinant vectors or knockdown by SRPK2 small interfering RNA (siRNA). The cells were stimulated by lipopolysaccharide (LPS) + interferon-γ (IFN-γ) or Aβ in vitro, generating inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin (IL)-10, and IL-6], which were investigated by real-time quantitative PCR (qPCR) and ELISA. The proliferation ability of the BV2 cells with/without SRPK2 expression was evaluated by WST-1 under pressure in the presence of Aβ. The effects of SRPK2 on microglia polarization were evaluated by investigating the expression of CD16/32 and CD206 by western blot and the expression of ionized calcium-binding adapter molecule-1 (IBA-1) and arginase-1 (Arg-1) by immunofluorescence. Hippocampal cells HT-22 were cultured with a BV2 cell (with/without SRPK2 expression)-derived medium stimulated by Aβ or LPS + IFN-γ, prior to the evaluation of HT-22 cytotoxicity by assessment of cell viability. Possible relationships between Akt and SRPK2 in the BV2 cells were investigated by western blot.ResultsThe expression of SRPK2 was related to the phenotype polarization changes of microglia with increased expression of CD16/32 and IBA-1. The expression of proinflammatory cytokines IL-6 and TNF-α was increased, whereas the expression of anti-inflammatory cytokine IL-10 was decreased in the BV2 cells with SRPK2 overexpression. Moreover, with the expression enhancement of SRPK2, the BV2 cells had a higher proliferation rate. Aβ treatment can promote SRPK2 expression in BV2 cells. Aβ or LPS + IFN-γ promoted the production of cytokines IL-6 and TNF-α but decreased cytokine IL-10 in the BV2 cells. SRPK2 deficiency alleviated the cytotoxic effects of Aβ or LPS + IFN-γ exposed microglia on HT22 cells. In addition, the activated Akt pathway promoted the expression of SRPK2 in the BV2 cells.ConclusionOur data have found that enhanced SRPK2 expression contributed to the proinflammatory activation of microglia. Thus, SRPK2 may be a key modulating pathway of inflammatory mediators in AD pathology.
| S-EPMC8831369 | biostudies-literature
Project description:Frontotemporal lobar degeneration, the neuropathological substrate of frontotemporal dementia (FTD), is characterized by the deposition of protein aggregates, including tau. Evidence has shown concomitant amyloid pathology in some of these patients, which seems to contribute to a more aggressive disease. Our aim was to evaluate cerebrospinal fluid (CSF) amyloid-beta as a predictor of the mortality of FTD patients. We included 99 patients diagnosed with FTD-both behavioral and language variants-with no associated motor neuron disease, from whom a CSF sample was collected. These patients were followed prospectively in our center, and demographic and clinical data were obtained. The survival analysis was carried through a Cox regression model. Patients who died during follow up had a significantly lower CSF amyloid-beta1-42 than those who did not. The survival analysis demonstrated that an increased death rate was associated with a lower CSF amyloid-beta1-42 (HR = 0.999, 95% CI = [0.997, 1.000], p = 0.049). Neither demographic nor clinical variables, nor CSF total tau or p-tau were significantly associated with this endpoint. These results suggest that amyloid deposition in FTD patients may be associated with a higher mortality.
| S-EPMC6963225 | biostudies-literature
Project description:The development of tau-PET allows paired helical filament tau pathology to be visualized in vivo. Increased knowledge about conditions affecting the rate of tau accumulation could guide the development of therapies halting the progression of Alzheimer's disease. However, the factors modifying the rate of tau accumulation over time in Alzheimer's disease are still largely unknown. Large-scale longitudinal cohort studies, adjusting for baseline tau load, are needed to establish such risk factors. In the present longitudinal study, 419 participants from four cohorts in the USA (Avid 05e, n = 157; Expedition-3, n = 82; ADNI, n = 123) and Sweden (BioFINDER, n = 57) were scanned repeatedly with tau-PET. The study participants were cognitively unimpaired (n = 153), or patients with mild cognitive impairment (n = 139) or Alzheimer's disease dementia (n = 127). Participants underwent two to four tau-PET (18F-flortaucipir) scans with a mean (± standard deviation) of 537 (±163) days between the first and last scan. The change in tau-PET signal was estimated in temporal meta- and neocortical regions of interest. Subject specific tau-PET slopes were predicted simultaneously by age, sex, amyloid status (determined by amyloid-β PET), APOE ε4 genotype, study cohort, diagnosis and baseline tau load. We found that accelerated increase in tau-PET signal was observed in amyloid-β-positive mild cognitive impairment (3.0 ± 5.3%) and Alzheimer's disease dementia (2.9 ± 5.7%), respectively, when compared to either amyloid-β-negative cognitively unimpaired (0.4 ± 2.7%), amyloid-β-negative mild cognitive impairment (-0.4 ± 2.3%) or amyloid-β-positive cognitively unimpaired (1.2 ± 2.8%). Tau-PET uptake was accelerated in females (temporal region of interest: t = 2.86, P = 0.005; neocortical region of interest: t = 2.90, P = 0.004), younger individuals (temporal region of interest: t = -2.49, P = 0.013), and individuals with higher baseline tau-PET signal (temporal region of interest: t = 3.83, P < 0.001; neocortical region of interest: t = 5.01, P < 0.001). Tau-PET slopes decreased with age in amyloid-β-positive subjects, but were stable by age in amyloid-β-negative subjects (age × amyloid-β status interaction: t = -2.39, P = 0.018). There were no effects of study cohort or APOE ε4 positivity. In a similar analysis on longitudinal amyloid-β-PET (in ADNI subjects only, n = 639), we found significant associations between the rate of amyloid-β accumulation and APOE ε4 positivity, older age and baseline amyloid-β positivity, but no effect of sex. In conclusion, in this longitudinal PET study comprising four cohorts, we found that the tau accumulation rate is greater in females and younger amyloid-β-positive individuals, while amyloid-β accumulation is greater in APOE ε4 carriers and older individuals. These findings are important considerations for the design of clinical trials, and might improve our understanding of factors associated with faster tau aggregation and spread.
| S-EPMC7805812 | biostudies-literature
Project description:Accumulating evidence indicates that neuroinflammation contributes to the pathogenesis and exacerbation of neurodegenerative disorders, such as Alzheimer's disease (AD). Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid that regulates many pathophysiological processes including inflammation. We present evidence here that the spinster homolog 2 (Spns2), a S1P transporter, promotes microglia pro-inflammatory activation in vitro and in vivo. Spns2 knockout (Spns2KO) in primary cultured microglia resulted in significantly reduced levels of pro-inflammatory cytokines induced by lipopolysaccharide (LPS) and amyloid-beta peptide 1-42 oligomers (A?42) when compared with littermate controls. Fingolimod (FTY720), a S1P receptor 1 (S1PR1) functional antagonist and FDA approved drug for relapsing-remitting multiple sclerosis, partially blunted A?42-induced pro-inflammatory cytokine generation, suggesting that Spns2 promotes microglia pro-inflammatory activation through S1P-signaling. Spns2KO significantly reduced A?42-induced nuclear factor kappa B (NF?B) activity. S1P increased, while FTY720 dampened, A?42-induced NF?B activity, suggesting that Spns2 activates microglia inflammation through, at least partially, NF?B pathway. Spns2KO mouse brains showed significantly reduced A?42-induced microglia activation/accumulation and reduced levels of pro-inflammatory cytokines when compared with age-matched controls. More interestingly, Spns2KO ameliorated A?42-induced working memory deficit detected by Y-Maze. In summary, these results suggest that Spns2 promotes pro-inflammatory polarization of microglia and may play a crucial role in AD pathogenesis.
| S-EPMC6355341 | biostudies-literature
Project description:Mind-body interventions such as mindfulness-based stress reduction (MBSR) may improve well-being by increasing awareness and regulation of physiological and cognitive states. However, it is unclear how practice may alter long-term, baseline physiological processes, and whether these changes reflect improved well-being. Using respiration rate (RR), which can be sensitive to effects of meditation, and 3 aspects of self-reported well-being (psychological well-being [PWB], distress, and medical symptoms), we tested pre-registered hypotheses that: (1) Lower baseline RR (in a resting, non-meditative state) would be a physiological marker associated with well-being, (2) MBSR would decrease RR, and (3) Training-related decreases in RR would be associated with improved well-being. We recruited 245 adults (age range = 18-65, M = 42.4): experienced meditators (n = 42), and meditation-naïve participants randomized to MBSR (n = 72), active control (n = 41), or waitlist control (n = 66). Data were collected at pre-randomization, post-intervention (or waiting), and long-term follow-up. Lower baseline RR was associated with lower psychological distress among long-term meditators (p* = 0.03, b = 0.02, 95% CI [0.01, 0.03]), though not in non-meditators prior to training. MBSR decreased RR compared to waitlist (p = 0.02, Cohen's d = - 0.41, 95% CI [- 0.78, - 0.06]), but not the active control. Decreased RR related to decreased medical symptoms, across all participants (p* = 0.02, b = 0.57, 95% CI [0.15, 0.98]). Post-training, lower RR was associated with higher PWB across training groups compared to waitlist (p* = 0.01, b = 0.06, 95% CI [0.02, 0.10]), though there were no significant differences in change in PWB between groups. This physiological marker may indicate higher physical and/or psychological well-being in those who engage in wellness practices.
| S-EPMC10518325 | biostudies-literature
Project description:Neuroinflammation is associated with Alzheimer's disease, but the application of cerebrospinal fluid measures of inflammatory proteins may be limited by overlapping pathways and relationships between them. In this work, we measure 15 cerebrospinal proteins related to microglial and T-cell functions, and show them to reproducibly form functionally-related groups within and across diagnostic categories in 382 participants from the Alzheimer's Disease Neuro-imaging Initiative as well participants from two independent cohorts. We further show higher levels of proteins related to soluble tumor necrosis factor receptor 1 are associated with reduced risk of conversion to dementia in the multi-centered (p = 0.027) and independent (p = 0.038) cohorts of people with mild cognitive impairment due to predicted Alzheimer's disease, while higher soluble TREM2 levels associated with slower decline in the dementia stage of Alzheimer's disease. These inflammatory proteins thus provide prognostic information independent of established Alzheimer's markers.
| S-EPMC8238986 | biostudies-literature
Project description:The ABCB1 gene, coding for the efflux transporter P-glycoprotein (PGP), is a candidate gene for Alzheimer disease (AD). P-glycoprotein is heavily expressed at the blood-brain barrier, where it mediates the efflux of ?-amyloid (A?) from the brain. In this study, we investigated a possible association between 2 common ABCB1 polymorphisms, G2677T/A (Ala893Ser/Thr) and C3435T, AD, and cerebrospinal fluid (CSF) levels of A?. No strong evidence for association was found.
| S-EPMC3293495 | biostudies-literature
Project description:IntroductionWe tested if water exchange across the blood-brain barrier (BBB), estimated with a noninvasive magnetic resonance imaging (MRI) technique, is associated with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) and neuropsychological function.MethodsForty cognitively normal older adults (67-86 years old) were scanned with diffusion-prepared, arterial spin labeling (DP-ASL), which estimates water exchange rate across the BBB (kw ). Participants also underwent CSF draw and neuropsychological testing. Multiple linear regression models were run with kw as a predictor of CSF concentrations and neuropsychological scores.ResultsIn multiple brain regions, BBB kw was positively associated with CSF amyloid beta (Aβ)42 concentration levels. BBB kw was only moderately associated with neuropsychological performance.DiscussionOur results suggest that low water exchange rate across the BBB is associated with low CSF Aβ42 concentration. These findings suggest that kw may be a promising noninvasive indicator of BBB Aβ clearance functions, a possibility which should be further tested in future research.
| S-EPMC8717840 | biostudies-literature
Project description:Background: Worldwide, coffee is one of the most popular beverages consumed. Several studies have suggested a protective role of coffee, including reduced risk of Alzheimer's disease (AD). However, there is limited longitudinal data from cohorts of older adults reporting associations of coffee intake with cognitive decline, in distinct domains, and investigating the neuropathological mechanisms underpinning any such associations. Methods: The aim of the current study was to investigate the relationship between self-reported habitual coffee intake, and cognitive decline assessed using a comprehensive neuropsychological battery in 227 cognitively normal older adults from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study, over 126 months. In a subset of individuals, we also investigated the relationship between habitual coffee intake and cerebral Aβ-amyloid accumulation (n = 60) and brain volumes (n = 51) over 126 months. Results: Higher baseline coffee consumption was associated with slower cognitive decline in executive function, attention, and the AIBL Preclinical AD Cognitive Composite (PACC; shown reliably to measure the first signs of cognitive decline in at-risk cognitively normal populations), and lower likelihood of transitioning to mild cognitive impairment or AD status, over 126 months. Higher baseline coffee consumption was also associated with slower Aβ-amyloid accumulation over 126 months, and lower risk of progressing to "moderate," "high," or "very high" Aβ-amyloid burden status over the same time-period. There were no associations between coffee intake and atrophy in total gray matter, white matter, or hippocampal volume. Discussion: Our results further support the hypothesis that coffee intake may be a protective factor against AD, with increased coffee consumption potentially reducing cognitive decline by slowing cerebral Aβ-amyloid accumulation, and thus attenuating the associated neurotoxicity from Aβ-amyloid-mediated oxidative stress and inflammatory processes. Further investigation is required to evaluate whether coffee intake could be incorporated as a modifiable lifestyle factor aimed at delaying AD onset.
| S-EPMC8641656 | biostudies-literature