TREM2 Deficiency Disrupts Network Oscillations Leading to Epileptic Activity and Aggravates Amyloid-β-Related Hippocampal Pathophysiology in Mice

2021 ◽  
pp. 1-11
Author(s):  
Milan Stoiljkovic ◽  
Karel Otero Gutierrez ◽  
Craig Kelley ◽  
Tamas L. Horvath ◽  
Mihály Hajós
Keyword(s):  
Neuronal Excitability ◽  
Amyloid Β ◽  
Epileptic Activity ◽  
Potential Contribution ◽  
Wild Type ◽  
Network Oscillations ◽  
Increased Risk ◽  
Hippocampal Network ◽  
The Impact ◽  
Tg2576 Mice

Background: Genetic mutations in triggering receptor expressed on myeloid cells-2 (TREM2) have been strongly associated with increased risk of developing Alzheimer’s disease (AD) and other progressive dementias. In the brain, TREM2 protein is specifically expressed on microglia suggesting their active involvement in driving disease pathology. Using various transgenic AD models to interfere with microglial function through TREM2, several recent studies provided important data indicating a causal link between TREM2 and underlying amyloid-β (Aβ) and tau pathology. However, mechanisms by which TREM2 contributes to increased predisposition to clinical AD and influences its progression still remain largely unknown. Objective: Our aim was to elucidate the potential contribution of TREM2 on specific oscillatory dynamic changes associated with AD pathophysiology. Methods: Spontaneous and brainstem nucleus pontis oralis stimulation-induced hippocampal oscillation paradigm was used to investigate the impact of TREM2 haploinsufficiency TREM2(Het) or total deficiency TREM2(Hom) on hippocampal network function in wild-type and Aβ overproducing Tg2576 mice under urethane anesthesia. Results: Partial (TREM2(Het)) or total (TREM2(Hom)) deletion of TREM2 led to increased incidence of spontaneous epileptiform seizures in both wild-type and Tg2576 mice. Importantly, deficiency of TREM2 in Tg2576 mice significantly diminished power of theta oscillation in the hippocampus elicited by brainstem-stimulation compared to wild-type mice. However, it did not affect hippocampal theta-phase gamma-amplitude coupling significantly, since over a 60%reduction was found in coupling in Tg2576 mice regardless of TREM2 function. Conclusion: Our findings indicate a role for TREM2-dependent microglial function in the hippocampal neuronal excitability in both wild type and Aβ overproducing mice, whereas deficiency in TREM2 function exacerbates disruptive effects of Aβ on hippocampal network oscillations.

scholarly journals High Dietary Iron Disrupts Iron Homeostasis and Induces Amyloid-β and Phospho-τ Expression in the Hippocampus of Adult Wild-Type and APP/PS1 Transgenic Mice

2019 ◽  
Vol 149 (12) ◽  
pp. 2247-2254 ◽  
Author(s):  
Min Chen ◽  
Jiashuo Zheng ◽  
Guohao Liu ◽  
Chong Zeng ◽  
En Xu ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Transgenic Mice ◽  
Iron Homeostasis ◽  
Iron Concentration ◽  
Amyloid Β ◽  
Dietary Iron ◽  
Wild Type ◽  
Brain Iron ◽  
Sod Activity ◽  
The Impact

ABSTRACT Background Brain iron deposition is a feature of Alzheimer disease and may contribute to its development. However, the relative contribution of dietary iron remains unclear. Objectives We investigated the impact of high dietary iron on brain pathological changes and cognitive function in adult wild-type (WT) mice and amyloid precursor protein/presenilin 1 (APP/PS1) double transgenic mice. Methods Male WT mice and APP/PS1 mice aged 10 wk were fed either a control diet (66 mg Fe/kg) (WT-Ctrl and APP/PS1-Ctrl) or a high iron diet (14 g Fe/kg) (WT-High Fe and APP/PS1-High Fe) for 20 wk. Iron concentrations in brain regions were measured by atomic absorption spectrophotometry. Brain iron staining and amyloid-β (Aβ) immunostaining were performed. Protein expressions in the hippocampus were determined by immunoblotting. Superoxide dismutase (SOD) activity and malondialdehyde concentration were examined. Cognitive functions were tested with the Morris water maze system. Results In the hippocampus, APP/PS1-High Fe mice had significantly higher iron concentration (2.5-fold) and ferritin (2.0-fold) than APP/PS1-Ctrl mice (P < 0.001), and WT-High Fe mice had significantly higher ferritin (2.0-fold) than WT-Ctrl mice (P < 0.001). Interestingly, APP/PS1 mice had significantly higher iron concentration (2–3-fold) and ferritin (2–2.5-fold) than WT mice fed either diet (P < 0.001). Histological analysis indicated that iron accumulated in the hippocampal dentate gyrus region in APP/PS1 mice, consistent with the pattern of Aβ deposition. For both mouse strains, iron treatment induced Aβ and phospho-τ expression (1.5–3-fold) in the hippocampus, but had little impact on oxidative stress and cognitive function. Furthermore, APP/PS1 mice had significantly lower SOD activity and higher malondialdehyde concentration than WT mice in the hippocampus (P < 0.0001), paralleled by apparent cognitive dysfunction. Conclusions Dietary iron overload induces iron disorder and Aβ and phospho-τ expression in the hippocampus of adult WT and APP/PS1 transgenic mice.

scholarly journals Amyloid β oligomer selective antibodies for Alzheimers therapeutics and diagnostics

2021 ◽  
Author(s):  
Kirsten L Viola ◽  
Maira A Bicca ◽  
Adrian M Bebenek ◽  
Daniel L Kranz ◽  
Vikas Nandwana ◽  
...  
Keyword(s):  
Memory Loss ◽  
Amyloid Β ◽  
Intraventricular Injection ◽  
Post Inoculation ◽  
Wild Type ◽  
Memory Dysfunction ◽  
Imaging Methods ◽  
5Xfad Mice ◽  
The Impact

Improvements have been made in the diagnosis of Alzheimer's disease (AD), manifesting mostly in the development of in vivo imaging methods that allow for the detection of pathological changes in AD by MRI and PET scans. Many of these imaging methods, however, use agents that probe amyloid fibrils and plaques- species that do not correlate well with disease progression and are not present at the earliest stages of the disease. Amyloid β oligomers (AβOs), rather, are now widely accepted as the Aβ species most germane to AD onset and progression. Here we report evidence further supporting the role of AβOs as pathological instigators of AD and introduce a promising anti-AβO diagnostic probe capable of distinguishing the 5xFAD mouse model from wild type mice by PET and MRI. In a developmental study, Aβ oligomers in 5xFAD mice were found to appear at 3 months of age, just prior to the onset of memory dysfunction, and spread as memory worsened. The increase is prominent in the subiculum and correlates with concomitant development of reactive astrocytosis. The impact of these AβOs on memory is in harmony with findings that intraventricular injection of synthetic AβOs into wild type mice induced hippocampal dependent memory dysfunction within 24 hours. Compelling support for the conclusion that endogenous AβOs cause memory loss was found in experiments showing that intranasal inoculation of AβO-selective antibodies into 5xFAD mice completely restored memory function, measured 30 days post-inoculation. These antibodies, which were modified to give MRI and PET imaging probes, were able to distinguish 5xFAD mice from wild type littermates. These results provide strong support for the role of AβOs in instigating memory loss and salient AD neuropathology, and they demonstrate that AβO selective antibodies have potential both for therapeutics and for diagnostics.

Alpha-Catenin Is Dispensable for Normal Hematopoietic Stem Cell Function.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1438-1438
Author(s):  
Natallia Mikhalkevich ◽  
Michael W. Becker
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Conflicts Of Interest ◽  
Fusion Product ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Myeloid Neoplasms ◽  
Increased Risk ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 1438 Poster Board I-461 We previously demonstrated the loss of expression of alpha-E-Catenin, the product of the CTNNA1 gene, in primary leukemic stem cells isolated from patients with advanced Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) associated with loss of all or part of the long arm of chromosome 5. To formally assess the impact of loss of Ctnna1 expression on hematopoiesis, we employed a murine model for the hematopoietic specific conditional loss of Ctnna1 expression. We demonstrate that Ctnna1 deficiency is associated with normal hematopoietic maturation and proliferation as assessed by peripheral blood examination and methycellulose colony assays. We assessed stem cell and early progenitor frequencies using both flow cytometry and functional assays. Ctnna1 deficiency was associated with equivalent frequencies of Sca1+C-Kit+CD135-Lineage- HSCs in both experimental animals and controls. Short term HSC and MPP frequencies were likewise unaltered. We assessed HSC function using transplantation studies. In competitive repopulation experiments, HSCs deficient for Ctnna1 maintained stable engraftment of recipient mice for up to 1 year. Limiting dilution analyses detected no significant difference in HSC frequency between wild type and Ctnna1 deficient mice. We examined the potential role of Ctnna1 deficient hematopoietic stem cells in two murine models for myeloid neoplasms 1.) exposure to mutagen ENU and 2.) a model for murine AML driven by the HoxA9-Nup98 fusion product. Following exposure of HSCs to ENU, loss of Ctnna1 was not associated with an increased risk of development of a myeloid neoplasm. Expression of the HoxA9-Nup98 fusion product by retroviral infection of Ctnna1 deficient and wild type Sca1+C-Kit+Lineage- cells resulted in no difference in time to development of the previously characterized myeloproliferative disorder or acute leukemia. Taken together, these data demonstrate that in the absence of specific genetic abnormalities, loss of Ctnna1 expression in primary murine HSCs is not associated with aberrant HSC function or the development of myeloid neoplasms. Further studies are necessary to define a role for of loss of Ctnna1 expression in human myeloid malignancies. Disclosures No relevant conflicts of interest to declare.

Traumatic Injury Reduces Amyloid Plaque Burden in the Transgenic 5xFAD Alzheimer’s Mouse Spinal Cord

2020 ◽  
Vol 77 (3) ◽  
pp. 1315-1330
Author(s):  
Tak-Ho Chu ◽  
Karen Cummins ◽  
Peter K. Stys
Keyword(s):  
Spinal Cord ◽  
Axonal Injury ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Amyloid Deposition ◽  
Plaque Burden ◽  
Wild Type ◽  
Plaque Deposition ◽  
5Xfad Mice ◽  
The Impact

Background: Axonal injury has been implicated in the development of amyloid-β in experimental brain injuries and clinical cases. The anatomy of the spinal cord provides a tractable model for examining the effects of trauma on amyloid deposition. Objective: Our goal was to examine the effects of axonal injury on plaque formation and clearance using wild type and 5xFAD transgenic Alzheimer’s disease mice. Methods: We contused the spinal cord at the T12 spinal level at 10 weeks, an age at which no amyloid plaques spontaneously accumulate in 5xFAD mice. We then explored plaque clearance by impacting spinal cords in 27-week-old 5xFAD mice where amyloid deposition is already well established. We also examined the cellular expression of one of the most prominent amyloid-β degradation enzymes, neprilysin, at the lesion site. Results: No plaques were found in wild type animals at any time points examined. Injury in 5xFAD prevented plaque deposition rostral and caudal to the lesion when the cords were examined at 2 and 4 months after the impact, whereas age-matched naïve 5xFAD mice showed extensive amyloid plaque deposition. A massive reduction in the number of plaques around the lesion was found as early as 7 days after the impact, preceded by neprilysin upregulation in astrocytes at 3 days after injury. At 7 days after injury, the majority of amyloid was found inside microglia/macrophages. Conclusion: These observations suggest that the efficient amyloid clearance after injury in the cord may be driven by the orchestrated efforts of astroglial and immune cells.

Abstract 161: Kcne2 Gene Deletion Combines With A Western Diet To Cause Early-onset Diabetes Mellitus And Atherosclerosis In Mice

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Soo-Min Lee ◽  
Ritu Kant ◽  
Geoffrey W Abbott
Keyword(s):  
Diabetes Mellitus ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Early Onset ◽  
Transmembrane Domain ◽  
Western Diet ◽  
Potential Contribution ◽  
Wild Type ◽  
Onset Diabetes ◽  
The Impact

The KCNE2 single transmembrane domain protein regulates multiple types of cardiac voltage-gated potassium (Kv) channel in vivo and its disruption causes the ventricular arrhythmia, Long QT Syndrome. Interestingly, a SNP near the human KCNE2 locus was also previously linked to early-onset myocardial infarction (MI). Because KCNE2 is also expressed outside the heart, we are interested in understanding extracardiac defects caused by Kcne2 deletion in mice, and also the potential contribution of these extracardiac defects to cardiac dysfunction. Thus, recently, we found that Kcne2 deletion creates a multifactorial substrate for sudden cardiac death (SCD) that includes diabetes mellitus and dyslipidemia. Because atherosclerosis is the most common cause of MI, here, using Kcne2 -/- mice, we investigated atherosclerosis and other potential predisposing factors in MI and SCD, and quantified the impact of a Western diet (high fat/high cholesterol) on these processes. Previously, we discovered impaired glucose tolerance in adult Kcne2 -/- mice using a standard glucose tolerance assay in which plasma glucose is quantified 0-2 hours following glucose injection. Here, we found that in Kcne2 -/- mice as young as 5 weeks, just 2 weeks on a Western diet induced impaired glucose tolerance, whereas 5-week-old wild-type mice regardless of diet, or Kcne2 -/- mice on a control diet, had normal glucose tolerance. This indicates a strong interaction between diet and Kcne2 deletion in creating early-onset diabetes mellitus. Atherosclerosis was also investigated, using Sudan IV staining of plaques in the aorta of wild-type and Kcne2 -/- mice fed on either standard (control) or Western diet. Strikingly, Kcne2 -/- mice as young as 4.5 months exhibited aortic plaques, and this was accelerated by a Western diet. In contrast, wild-type littermates did not exhibit plaques at this age, regardless of diet. Ongoing studies to determine potential metabolic defects in the liver and pancreas are aimed at understanding the molecular mechanisms underlying these findings. Our data provide further evidence of the unexpected complexity of monogenic cardiovascular syndromes caused by disruption of genes associated with cardiac arrhythmias.

scholarly journals Do ACE and ACE2 Polymorphisms Influence in the Pathogenesis of Diabetic Nephropathy?

2021 ◽  
Author(s):  
Angela Adamski da Silva Reis ◽  
Elisângela Gomes da Silva ◽  
Kamilla de Faria Santos ◽  
Laura Raniere Borges dos Anjos ◽  
Rodrigo da Silva Santos ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Wild Type ◽  
Central Brazil ◽  
Increased Risk ◽  
Pcr Rflp ◽  
Patients With Diabetes ◽  
The Impact ◽  
Encoding Genes ◽  
Circulating Levels

Abstract BackgroundIn this study, we reported the impact of polymorphisms in the ACE and ACE2 encoding genes on diabetic nephropathy (DN) susceptibility in Brazilian subjects from the Goiânia region of central Brazil. These genes have been increasingly highlighted, mainly due to their relationship with the severity of COVID-19. Methods and ResultsIn this study, 196 diabetic individuals (101 patients with DN and 95 without DN) were investigated. Genotyping of the ACE gene was performed by real-time PCR, and ACE2 gene analysis was conducted through PCR/RFLP. Our results indicate that the I/D genotype presented increased risk in the development of DN (OR=2.5; p=0.01). This finding shows the D allele influences the circulating levels of angiotensin II and, as a consequence, arterial pressure increases, the glomeruli will be affected, culminating in glomerular damage and, consequently, DN. By combining ACE and ACE2 genotypes, we observed an evident risk tendency (OR=2.51; p=0.07) associated with the combination of ACE (I/D or D/D) and wild type ACE2 (GG) polymorphisms, as well as for the combination of the same polymorphism and ACE2 heterozygous or mutant (GA or AA or A) (OR=2.61; p=0.08). ConclusionsOur findings suggest that ACE polymorphism could have an important role in the DN pathogenesis, as well as in the variations of the clinical parameters investigated in this research. However, ACE2 polymorphism was not correlated with DN. Thus, characterization of ACE and ACE2 polymorphisms in patients with Diabetes Mellitus need more studies for appropriate and effective clinical conducts based in genotype.

The Impact of the hAPP695SW Transgene and Associated Amyloid-β Accumulation on Murine Hippocampal Biochemical Pathways

2021 ◽  
pp. 1-19
Author(s):  
Mona Khorani ◽  
Gerd Bobe ◽  
Donald G. Matthews ◽  
Armando Alcazar Magana ◽  
Maya Caruso ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Redox Regulation ◽  
Amyloid Β ◽  
Tg2576 Mouse ◽  
Wild Type ◽  
Biochemical Pathways ◽  
Lower Fatty Acid ◽  
Hippocampal Tissue ◽  
The Impact ◽  
The Brain

Background: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ) peptide in the brain. Objective: Gain a better insight into alterations in major biochemical pathways underlying AD. Methods: We compared metabolomic profiles of hippocampal tissue of 20-month-old female Tg2576 mice expressing the familial AD-associated hAPP695SW transgene with their 20-month-old wild type female littermates. Results: The hAPP695SW transgene causes overproduction and accumulation of Aβ in the brain. Out of 180 annotated metabolites, 54 metabolites differed (30 higher and 24 lower in Tg2576 versus wild-type hippocampal tissue) and were linked to the amino acid, nucleic acid, glycerophospholipid, ceramide, and fatty acid metabolism. Our results point to 1) heightened metabolic activity as indicated by higher levels of urea, enhanced fatty acid β-oxidation, and lower fatty acid levels; 2) enhanced redox regulation; and 3) an imbalance of neuro-excitatory and neuro-inhibitory metabolites in hippocampal tissue of aged hAPP695SW transgenic mice. Conclusion: Taken together, our results suggest that dysregulation of multiple metabolic pathways associated with a concomitant shift to an excitatory-inhibitory imbalance are contributing mechanisms of AD-related pathology in the Tg2576 mouse.

scholarly journals The Structures of the E22Δ Mutant-Type Amyloid-β Alloforms and the Impact of E22Δ Mutation on the Structures of the Wild-Type Amyloid-β Alloforms

2012 ◽  
Vol 4 (2) ◽  
pp. 310-320 ◽  
Author(s):  
Orkid Coskuner ◽  
Olivia Wise-Scira ◽  
George Perry ◽  
Taizo Kitahara
Keyword(s):  
Amyloid Β ◽  
Wild Type ◽  
Mutant Type ◽  
The Impact

scholarly journals TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques

2016 ◽  
Vol 213 (5) ◽  
pp. 667-675 ◽  
Author(s):  
Yaming Wang ◽  
Tyler K. Ulland ◽  
Jason D. Ulrich ◽  
Wilbur Song ◽  
John A. Tzaferis ◽  
...  
Keyword(s):  
Neuronal Degeneration ◽  
Myeloid Cells ◽  
Amyloid Β ◽  
Early Time ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Increased Risk ◽  
5Xfad Mice ◽  
Microglial Response ◽  
The Impact

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor that recognizes changes in the lipid microenvironment, which may occur during amyloid β (Aβ) accumulation and neuronal degeneration in Alzheimer’s disease (AD). Rare TREM2 variants that affect TREM2 function lead to an increased risk of developing AD. In murine models of AD, TREM2 deficiency prevents microglial clustering around Aβ deposits. However, the origin of myeloid cells surrounding amyloid and the impact of TREM2 on Aβ accumulation are a matter of debate. Using parabiosis, we found that amyloid-associated myeloid cells derive from brain-resident microglia rather than from recruitment of peripheral blood monocytes. To determine the impact of TREM2 deficiency on Aβ accumulation, we examined Aβ plaques in the 5XFAD model of AD at the onset of Aβ-related pathology. At this early time point, Aβ accumulation was similar in TREM2-deficient and -sufficient 5XFAD mice. However, in the absence of TREM2, Aβ plaques were not fully enclosed by microglia; they were more diffuse, less dense, and were associated with significantly greater neuritic damage. Thus, TREM2 protects from AD by enabling microglia to surround and alter Aβ plaque structure, thereby limiting neuritic damage.

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