scholarly journals Curcugreen Treatment Prevented Splenomegaly and Other Peripheral Organ Abnormalities in 3xTg and 5xFAD Mouse Models of Alzheimer’s Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 899
Author(s):  
Jayeeta Manna ◽  
Gary L. Dunbar ◽  
Panchanan Maiti
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Amyloid Deposition ◽  
Tunel Staining ◽  
Western Blots ◽  
Peripheral Organ ◽  
Apoptotic Death ◽  
Anti Inflammatory ◽  
5Xfad Mice

Metabolic dysfunction and immune disorders are common in Alzheimer’s disease (AD). The mechanistic details of these epiphenomena in AD are unclear. Here, we have investigated whether a highly bioavailable curcuminoid formulation, curcugreen (CGR), can prevent abnormalities in peripheral organs of two mouse models of AD. Eighteen- and 24-month-old male and female 3xTg and 5xFAD mice were treated with CGR (100 mg/kg) for 2 months, orally. Cytoarchitectural changes of spleen, liver, kidney and lungs were studied by H&E stain. Apoptotic death was confirmed by TUNEL staining. Amyloid deposition, pTau levels, proinflammatory, anti-inflammatory and cell death/survival markers were studied by Western blots. Curcugreen reduced the observed splenomegaly (3xTg) and degeneration of spleen, granulomatous inflammation in the kidney, hepatic sinusoidal disorganization, hepatocellular hypertrophy, inflammation of the central hepatic vein, infiltration and swelling of lung tissues, and apoptotic death in all these areas in both 3xTg and 5xFAD mice. Similarly, CGR decreased amyloid deposition, pTau, proinflammatory markers, cell loss and decrements in anti-inflammatory markers in both 3xTg and 5xFAD mice. Peripheral organ abnormalities and inflammatory responses in AD were ameliorated by curcuminoid treatment.

scholarly journals Ageing-associated myelin dysfunction drives amyloid deposition in mouse models of Alzheimer's disease

2021 ◽  
Author(s):  
Constanze Depp ◽  
Ting Sun ◽  
Andrew Octavian Sasmita ◽  
Lena Spieth ◽  
Stefan A. Berghoff ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Mouse Models ◽  
Structural Integrity ◽  
Amyloid Β ◽  
Amyloid Deposition ◽  
Structural Defects ◽  
Light Sheet Microscopy ◽  
Brain Ageing

The prevalence of Alzheimer's disease (AD), the leading cause of dementia, shows a strict age-dependency, but why ageing constitutes the main risk factor for this disease is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths, the latter associated with secondary neuroinflammation. Since oligodendrocytes support axonal and neuronal health, we hypothesised that ageing-associated loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the primary neuropathological hallmark of AD. Here, we show that in AD mouse models different genetically induced defects of myelin integrity or demyelinating injuries are indeed potent drivers of amyloid deposition in vivo, quantified by whole brain light sheet microscopy. Conversely, the lack of myelin in the forebrain provides protection against plaque deposition. Mechanistically, we find that myelin dysfunction causes the accumulation of the Aβ producing machinery within axonal swellings and increases cortical amyloid precursor protein (APP) cleavage. Surprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia but show a disease-associated microglia (DAM)-like signature as revealed by bulk and single cell transcriptomics. These activated microglia, however, are primarily engaged with myelin, preventing the protective reactions of microglia to Aβ plaques. Our data suggest a working model, in which age-dependent structural defects of myelin promote plaque formation, directly and indirectly, and are thus an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay AD.

scholarly journals Neuroprotective and Anti-Inflammatory Effects of Low–Moderate Dose Ionizing Radiation in Models of Alzheimer’s Disease

2020 ◽  
Vol 21 (10) ◽  
pp. 3678 ◽  
Author(s):  
Sujin Kim ◽  
Yunkwon Nam ◽  
Chanyang Kim ◽  
Hyewon Lee ◽  
Seojin Hong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Ionizing Radiation ◽  
Pharmacological Intervention ◽  
Therapeutic Effects ◽  
Moderate Dose ◽  
Short Term ◽  
Anti Inflammatory ◽  
5Xfad Mice

Alzheimer’s disease (AD) is the most common cause of dementia. The neuropathological features of AD include amyloid-β (Aβ) deposition and hyperphosphorylated tau accumulation. Although several clinical trials have been conducted to identify a cure for AD, no effective drug or treatment has been identified thus far. Recently, the potential use of non-pharmacological interventions to prevent or treat AD has gained attention. Low-dose ionizing radiation (LDIR) is a non-pharmacological intervention which is currently being evaluated in clinical trials for AD patients. However, the mechanisms underlying the therapeutic effects of LDIR therapy have not yet been established. In this study, we examined the effect of LDIR on Aβ accumulation and Aβ-mediated pathology. To investigate the short-term effects of low–moderate dose ionizing radiation (LMDIR), a total of 9 Gy (1.8 Gy per fraction for five times) were radiated to 4-month-old 5XFAD mice, an Aβ-overexpressing transgenic mouse model of AD, and then sacrificed at 4 days after last exposure to LMDIR. Comparing sham-exposed and LMDIR-exposed 5XFAD mice indicated that short-term exposure to LMDIR did not affect Aβ accumulation in the brain, but significantly ameliorated synaptic degeneration, neuronal loss, and neuroinflammation in the hippocampal formation and cerebral cortex. In addition, a direct neuroprotective effect was confirmed in SH-SY5Y neuronal cells treated with Aβ1–42 (2 μM) after single irradiation (1 Gy). In BV-2 microglial cells exposed to Aβ and/or LMDIR, LMDIR therapy significantly inhibited the production of pro-inflammatory molecules and activation of the nuclear factor-kappa B (NF-κB) pathway. These results indicate that LMDIR directly ameliorated neurodegeneration and neuroinflammation in vivo and in vitro. Collectively, our findings suggest that the therapeutic benefits of LMDIR in AD may be mediated by its neuroprotective and anti-inflammatory effects.

scholarly journals Unique molecular characteristics and microglial origin of Kv1.3 channel–positive brain myeloid cells in Alzheimer’s disease

2021 ◽  
Vol 118 (11) ◽  
pp. e2013545118
Author(s):  
Supriya Ramesha ◽  
Sruti Rayaprolu ◽  
Christine A. Bowen ◽  
Cynthia R. Giver ◽  
Sara Bitarafan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Mononuclear Phagocytes ◽  
Molecular Characteristics ◽  
Cellular Origin ◽  
Molecular Features ◽  
Kv1.3 Channels ◽  
5Xfad Mice

Kv1.3 potassium channels, expressed by proinflammatory central nervous system mononuclear phagocytes (CNS-MPs), are promising therapeutic targets for modulating neuroinflammation in Alzheimer’s disease (AD). The molecular characteristics of Kv1.3-high CNS-MPs and their cellular origin from microglia or CNS-infiltrating monocytes are unclear. While Kv1.3 blockade reduces amyloid beta (Aβ) burden in mouse models, the downstream immune effects on molecular profiles of CNS-MPs remain unknown. We show that functional Kv1.3 channels are selectively expressed by a subset of CD11b+CD45+ CNS-MPs acutely isolated from an Aβ mouse model (5xFAD) as well as fresh postmortem human AD brain. Transcriptomic profiling of purified CD11b+Kv1.3+ CNS-MPs, CD11b+CD45int Kv1.3neg microglia, and peripheral monocytes from 5xFAD mice revealed that Kv1.3-high CNS-MPs highly express canonical microglial markers (Tmem119, P2ry12) and are distinct from peripheral Ly6chigh/Ly6clow monocytes. Unlike homeostatic microglia, Kv1.3-high CNS-MPs express relatively lower levels of homeostatic genes, higher levels of CD11c, and increased levels of glutamatergic transcripts, potentially representing phagocytic uptake of neuronal elements. Using irradiation bone marrow CD45.1/CD45.2 chimerism in 5xFAD mice, we show that Kv1.3+ CNS-MPs originate from microglia and not blood-derived monocytes. We show that Kv1.3 channels regulate membrane potential and early signaling events in microglia. Finally, in vivo blockade of Kv1.3 channels in 5xFAD mice by ShK-223 reduced Aβ burden, increased CD11c+ CNS-MPs, and expression of phagocytic genes while suppressing proinflammatory genes (IL1b). Our results confirm the microglial origin and identify unique molecular features of Kv1.3-expressing CNS-MPs. In addition, we provide evidence for CNS immunomodulation by Kv1.3 blockers in AD mouse models resulting in a prophagocytic phenotype.

scholarly journals Liraglutide Has Anti-Inflammatory and Anti-Amyloid Properties in Streptozotocin-Induced and 5xFAD Mouse Models of Alzheimer’s Disease

2021 ◽  
Vol 22 (2) ◽  
pp. 860
Author(s):  
Leela Paladugu ◽  
Abeer Gharaibeh ◽  
Nivya Kolli ◽  
Cameron Learman ◽  
Tia C. Hall ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Insulin Signaling ◽  
Epidemiological Studies ◽  
Disease Stage ◽  
Brain State ◽  
Cognitive Changes ◽  
Neuroprotective Effects ◽  
Anti Inflammatory

Recent clinical and epidemiological studies support the contention that diabetes mellitus (DM) is a strong risk factor for the development of Alzheimer’s disease (AD). The use of insulin cell toxin, streptozotocin (STZ), when injected into the lateral ventricles, develops an insulin resistant brain state (IRBS) and represents a non-transgenic, or sporadic AD model (SAD), with several AD-like neuropathological features. The present study explored the effects of an anti-diabetic drug, liraglutide (LIR), in reversing major pathological hallmarks in the prodromal disease stage of both the 5xFAD transgenic and SAD mouse models of AD. Three-month-old 5xFAD and age-matched wild type mice were given a single intracerebroventricular (i.c.v) injection of STZ or vehicle (saline) and were subsequently treated with LIR, intraperitoneally (IP), once a day for 30 days. The extent of neurodegeneration, Aβ plaque load, and key proteins associated with the insulin signaling pathways were measured using Western blot and neuroinflammation (via immunohistological assays) in the cortical and hippocampal regions of the brain were assessed following a series of behavioral tests used to measure cognitive function after LIR or vehicle treatments. Our results indicated that STZ significantly increased neuroinflammation, Aβ plaque deposition and disrupted insulin signaling pathway, while 25 nmol/kg LIR, when injected IP, significantly decreased neuroinflammatory responses in both SAD and 5xFAD mice before significant cognitive changes were observed, suggesting LIR can reduce early neuropathology markers prior to the emergence of overt memory deficits. Our results indicate that LIR has neuroprotective effects and has the potential to serve as an anti-inflammatory and anti-amyloid prophylactic therapy in the prodromal stages of AD.

scholarly journals Aging Related Transcriptomic Changes in the Mouse Models of Alzheimer’s Disease

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 117-117
Author(s):  
Asli Uyar ◽  
Ravi Pandey ◽  
Christoph Preuss ◽  
Kevin Kotredes ◽  
Gareth Howell ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Late Onset ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Aging Research ◽  
5Xfad Mice ◽  
Transcriptomic Changes ◽  
The Brain

Abstract Alzheimer’s Disease (AD) is characterized by multiple clinical phenotypes and molecular signatures at different stages of the disease and aging is the major risk factor for sporadic AD. Aging and AD are linked at molecular, cellular and systems level with commonalities in inflammation and associated immune response in the brain. Mouse models of AD were developed that mimic various aspects of aging-associated neurodegeneration and inflammation. Research in mouse models of AD showed that drugs and treatments designed for AD can decelerate aging phenotypes suggesting efficient utilization of these models in aging research. We analyzed RNA-Seq transcriptomic data from transgenic mouse models of familial AD (APP/PS1 and 5XFAD) and knock-in mouse models of late-onset AD (APOE and TREM2) at the ages between 4-months and 24-months. The number of differentially expressed genes between transgenic/knock-in and WT mice increased by age in all mouse models. Gene set enrichment analysis identified metabolic pathways, including oxidative phosphorylation, altered in an age and genotype related manner in the brain of APP/PS1 and 5XFAD mice that recapitulate major features of amyloid pathology. Immunity related pathways were enriched in APOE4 model carrying Trem2*R47H mutation at >12 months-old. We also mapped the transcriptional signatures to co-expression gene modules of human LOAD from the AMP-AD consortium and observed correlations specific to each mouse model. Our study provides a detailed view of how the aging interacts with AD-relevant pathologies at the transcriptome level and demonstrates potential translational relevance of the AD mouse models in the context of human aging.

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