Mariko Taga

Microglial immunophenotype in dementia with Alzheimer's pathology

BackgroundGenetic risk factors for Alzheimer’s disease imply that inflammation plays a causal role in development of the disease. Experimental studies suggest that microglia, as the brain macrophages, have diverse functions, with their main role in health being to survey the brain parenchyma through highly motile processes.MethodsUsing the Medical Research Council Cognitive Function and Ageing Studies resources, we have immunophenotyped microglia to investigate their role in dementia with Alzheimer’s pathology. Cerebral cortex obtained at post-mortem from 299 participants was analysed by immunohistochemistry for cluster of differentiation (CD)68 (phagocytosis), human leukocyte antigen (HLA)-DR (antigen-presenting function), ionized calcium-binding adaptor molecule (Iba1) (microglial motility), macrophage scavenger receptor (MSR)-A (plaque-related phagocytosis) and CD64 (immunoglobulin Fcγ receptor I).ResultsThe presence of dementia was associated positively with CD68 (P < 0.001), MSR-A (P = 0.010) and CD64 (P = 0.007) and negatively with Iba1 (P < 0.001). Among participants without dementia, the cognitive function according to the Mini-Mental State Examination was associated positively with Iba1 (P < 0.001) and negatively with CD68 (P = 0.033), and in participants with dementia and Alzheimer’s pathology, positively with all microglial markers except Iba1. Overall, in participants without dementia, the relationship with Alzheimer’s pathology was negative or not significant, and positive in participants with dementia and Alzheimer’s pathology. Apolipoprotein E (APOE) ε2 allele was associated with expression of Iba1 (P = 0.001) and MSR-A (P < 0.001) and APOE ε4 with CD68, HLA-DR and CD64 (P < 0.001).ConclusionsOur findings raise the possibility that in dementia with Alzheimer’s pathology, microglia lose motility (Iba-1) necessary to support neurons. Conversely, other microglial proteins (CD68, MSR-A), the role of which is clearance of damaged cellular material, are positively associated with Alzheimer’s pathology and impaired cognitive function. In addition, our data imply that microglia may respond differently to Aβ and tau in participants with and without dementia so that the microglial activity could potentially influence the likelihood of developing dementia, as supported by genetic studies, highlighting the complexity and diversity of microglial responses.

Metaflammasome components in the human brain: a role in dementia with alzheimer's pathology?

Epidemiological and genetic studies have identified metabolic disorders and inflammation as risk factors for Alzheimers disease (AD). Evidence in obesity and type‐2 diabetes suggests a role for a metabolic inflammasome (“metaflammasome”) in mediating chronic inflammation in peripheral organs implicating IKKβ (inhibitor of nuclear factor kappa‐B kinase subunit beta), IRS1 (insulin receptor substrate 1), JNK (c‐jun N‐terminal kinase), and PKR (double‐stranded RNA protein kinase). We hypothesized that these proteins are expressed in the brain in response to metabolic risk factors in AD. Neocortex from 299 participants from the MRC Cognitive Function and Ageing Studies was analysed by immunohistochemistry for the expression of the phosphorylated (active) form of IKKβ [pSer176/180], IRS1 [pS312], JNK [pThr183/Tyr185] and PKR [pT451]. The data were analyzed to investigate whether the proteins were expressed together and in relation with metabolic disorders, dementia, Alzheimers pathology and APOE genotype. We observed a change from a positive to a negative association between the proteins and hypertension according to the dementia status. Type‐2 diabetes was negatively related with the proteins among participants without dementia; whereas participants with dementia and AD pathology showed a positive association with JNK. A significant association between IKKβ and JNK in participants with dementia and AD pathology was observed, but not in those without dementia. Otherwise, weak to moderate associations were observed among the protein loads. The presence of dementia was significantly associated with JNK and negatively associated with IKKβ and IRS1. Cognitive scores showed a significant positive relationship with IKKβ and a negative with IRS1, JNK and PKR. The proteins were significantly associated with pathology in Alzheimers participants with the relationship being inverse or not significant in participants without dementia. Expression of the proteins was not related to APOE genotype. These findings highlight a role for these proteins in AD pathophysiology but not necessarily as a complex.

PKR modulates abnormal brain signaling in experimental obesity

Metabolic disorders including obesity and type 2 diabetes are known to be associated with chronic inflammation and are obvious risk factors for Alzheimer’s disease. Recent evidences concerning obesity and diabetes suggest that the metabolic inflammasome (“metaflammasome”) mediates chronic inflammation. The double-stranded RNA-dependent protein kinase (PKR) is a central component of the metaflammasome. In wild type (WT) and PKR-/- mice, blood glucose, insulin and lipid levels and the brain expression of the phosphorylated components of the metaflammasome—PKR, JNK, IRS1 and IKKbeta—were studied after the induction of obesity by a high fat diet (HFD). The results showed significant increased levels of activated brain metaflammasome proteins in exposed WT mice but the changes were not significant in PKR-/- mice. In addition, gain weight was observed in WT mice and also in PKR-/- mice exposed to HFD. Increased blood insulin level was more accentuated in PKR -/- mice. The modulation of PKR activity could be an appropriate therapeutic approach, aimed at reducing abnormal brain metabolism and inflammation linked to metabolic disorders in order to reduce the risk of neurodegeneration.

Performance and complications of lumbar puncture in memory clinics: Results of the multicenter lp feasibility study

mL, in combination with T-tau values >296.50 pg/mL and/or Ptau181P values >56.50 pg/mL. Both increments and decrements (+/-5%, +/-10%, +/-20%, +/-30%, +/-40%) were added to the true CSF biomarker values of the definite AD, and control subjects. Results: The clinical diagnostic accuracy remained well above the 80% threshold level when a bias in analyte concentrations between -20% and +20% were artificially introduced to all three true biomarker values of the definite AD and control subjects. If the range of biases was +/-30% or +/-40%, the diagnostic accuracy fell below the threshold of 80%, however if simulated variability was added to only one of the three biomarkers, the diagnostic accuracy remained above 80%. Conclusions: The clinical diagnostic accuracy of AD CSF biomarkers remained well above the 80% threshold level despite simulation of progressive variability in the range of +/20% of all three true biomarker values in autopsy-confirmed AD patients and cognitively healthy controls.

Investigation of the metaflammasome in the human brain: A cfas study

Mariko Taga, Thais Minett, James Nicoll, Carol Brayne, Paul Ince, Jacques Hugon, Delphine Boche, University of Southampton, Southampton, United Kingdom; University of Cambridge, Cambridge, United Kingdom; Cambridge Institute of Public Health, Cambridge, United Kingdom; University of Sheffield, Sheffield, United Kingdom; University of Paris Diderot/AP-HP, Paris, France; Inserm U942, Paris, France. Contact e-mail: mariko.taga@ outlook.com

Involvement of a cerebral “metaflammasome” in experimental obesity

Background:Neuropathologic confirmation of Alzheimer’s disease (AD) is considered secure with a Braak Stage1⁄46 at autopsy, strongly supported by a Braak stage1⁄45, weakly supported by a Braak stage1⁄44, and unlikely at lesser stages. Some decedents with Braak stages of 5 or 6 at autopsy had been cognitively normal during life. Others with a Braak stage of 4 had been definitely demented. Is there an explanation for such variation in cognitive resilience or vulnerability to the brain lesions of AD? Comprehensive research protocol brain autopsies on 774 decedent participants in the HAASwho had been evaluated for cognitive impairment during life provide opportunity to address this question. Methods: The Cognitive Abilities and Screening Instrument (CASI) was administered at 2-3 year intervals between 1991-2012, during which more than 90% of the 3734 participants died. The last CASI score within 3 years of death was used as a measure of cognitive functioning in the final years of life. Brain autopsies were done on decedent participants when death was identified and legal consent obtained within 72 hours. Results: Definite cognitive impairment (CASI<60) had been present in 83% of 41 autopsied decedents with a Braak stage1⁄4 6, 50% of 98 with Braak stage 1⁄45, and 41% of 128 with Braak stage1⁄4 4. Fully normal cognitive impairment (CASI>1⁄482) had existed in none of of those with Braak stage 1⁄46, in 15% with Braak1⁄45, and 23% with Braak1⁄44. Among the 98 decedents with Braak stage1⁄45, definite cognitive impairment in the years prior to death was significantly associated with several coprevalent non-AD brain lesions and/or generalized brain atrophy, shorter interval between final examination and death, and marginally with counts of neocortical neuritic amyloid plaques. Several other factors (head size, education, occupational complexity, late life depression, heart disease, etc.) were not significantly associated with cognitive impairment in decedents with Braak stages of 4, 5, or 6. Conclusions:Among HAAS decedents with autopsy Braak scores of 4, 5, or 6 (considered independently), resilience or vulnerability to cognitive impairment or dementia in the final years of life was significantly associated with three neuropathologic factors: coprevalent non-AD brain lesions, generalized brain atrophy, and neocortical neuritic plaque counts.

Peripheral inflammation increases PKR activation, Tau phosphorylation and amyloid β production in wild-type mice

Systemic inflammation is correlated with dementia progression. Pro-inflammatory molecules can communicate from the periphery to the central nervous system to induce neuroinflammation and neurodegeneration. Our protein of interest is the pro-apoptotic kinase PKR (the double strand-RNA dependent protein kinase). Increased activated PKR levels were found in AD patients brain and cerebrospinal fluid. PKR activation can be triggered by inflammatory stresses and induces neurotoxicity in vitro. Is in vivo PKR-mediated inflammation involved in AD neurodegenerative process?

Role of the PKR-eIF2α pathway in BACE1 levels Relevance in Alzheimer's disease

tides (Ab) and biometals in the brain represent a major pathogenic pathway in Alzheimer’s disease (AD) and provide the basis for clinical effective disease-modifying therapy (Duce and Bush, 2010; Lannfelt, 2008). Mapping the micro anatomical distribution of essential and trace elements and isotopes in the brain is essential for understanding AD pathobiology and designing new disease-modifying therapies. To date, mapping the brain metallome has been limited by technical barriers. Here we developed a new technique, High-Resolution Metallomic Imaging Mass Spectrometry (HRMIMS), to perform the first high-resolution multi-elemental and isotopic distribution maps of the brain metallome in the Tg2576 transgenic AD mouse model compared to wild-type control mice. Methods: Mice were procured from the Boston University Alzheimer’s Disease Center Transgenic Mouse Facility. Mouse brains were flash frozen and analyzed by metallomic imaging mass spectrometry (MIMS mapping) using a custom cryogenic cell coupled to nanosecond ultraviolet laser ablation (NULA) and hyphenated high-resolution magnetic sector field ICP-MS at the Boston University Center for Biometals & Metallomics, Boston, MA. Laser wavelength, 213 nm; rate, 5-50 mms-1; spot size: 10 micron (high resolution) to 100 micron (scanning resolution). MIMS analysis was conducted on surround to establish elemental background and calibrated with NIST standards. Results: High resolution metallomic maps generated from Tg2576 (Tg) and wild-type (Wt) mouse brain demonstrated unique elemental and isotopic distribution patterns. Zinc (Zn) brain maps revealed a distinctive distribution pattern marked by cortical lamination, prominent allocortical (hippocampus, amygdala) deposition, and isotopic (67Zn, 70Zn). This pattern was progressively disrupted in Tg mice as a function of age with abnormal Zn accumulation co-localizing with amyloid plaque and Timm’s staining. Simultaneous metallomic maps of the same Wt and Tg brains revealed distinctive elemental and isotopic distribution patterns for other important biometals, including copper (Cu), iron (Fe), selenium (Se), molybdenum (Mo), manganese (Mn), and others. Conclusions: We deployed HR-MIMS analysis to generate detailed quantitative high-resolution spatial distribution maps of essential and trace elements and isotopes in Tg2576 transgenic and wild-type mouse brain at 10-100 micron spatial resolution. This study strongly supports a role for zinc in AD-linked brain pathology.