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 MALT1 Controls Attenuated Rabies Virus by Inducing Early Inflammation and T Cell Activation in the Brain

2018 ◽  
Vol 92 (8) ◽  
Author(s):  
E. Kip ◽  
J. Staal ◽  
L. Verstrepen ◽  
H. G. Tima ◽  
S. Terryn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Infection ◽  
Rabies Virus ◽  
T Cell Activation ◽  
Therapeutic Target ◽  
Cell Activation ◽  
Wild Type ◽  
The Impact ◽  
The Brain

ABSTRACTMALT1 is involved in the activation of immune responses, as well as in the proliferation and survival of certain cancer cells. MALT1 acts as a scaffold protein for NF-κB signaling and a cysteine protease that cleaves substrates, further promoting the expression of immunoregulatory genes. Deregulated MALT1 activity has been associated with autoimmunity and cancer, implicating MALT1 as a new therapeutic target. Although MALT1 deficiency has been shown to protect against experimental autoimmune encephalomyelitis, nothing is known about the impact of MALT1 on virus infection in the central nervous system. Here, we studied infection with an attenuated rabies virus, Evelyn-Rotnycki-Abelseth (ERA) virus, and observed increased susceptibility with ERA virus in MALT1−/−mice. Indeed, after intranasal infection with ERA virus, wild-type mice developed mild transient clinical signs with recovery at 35 days postinoculation (dpi). Interestingly, MALT1−/−mice developed severe disease requiring euthanasia at around 17 dpi. A decreased induction of inflammatory gene expression and cell infiltration and activation was observed in MALT1−/−mice at 10 dpi compared to MALT1+/+infected mice. At 17 dpi, however, the level of inflammatory cell activation was comparable to that observed in MALT1+/+mice. Moreover, MALT1−/−mice failed to produce virus-neutralizing antibodies. Similar results were obtained with specific inactivation of MALT1 in T cells. Finally, treatment of wild-type mice with mepazine, a MALT1 protease inhibitor, also led to mortality upon ERA virus infection. These data emphasize the importance of early inflammation and activation of T cells through MALT1 for controlling the virulence of an attenuated rabies virus in the brain.IMPORTANCERabies virus is a neurotropic virus which can infect any mammal. Annually, 59,000 people die from rabies. Effective therapy is lacking and hampered by gaps in the understanding of virus pathogenicity. MALT1 is an intracellular protein involved in innate and adaptive immunity and is an interesting therapeutic target because MALT1-deregulated activity has been associated with autoimmunity and cancers. The role of MALT1 in viral infection is, however, largely unknown. Here, we study the impact of MALT1 on virus infection in the brain, using the attenuated ERA rabies virus in different models of MALT1-deficient mice. We reveal the importance of MALT1-mediated inflammation and T cell activation to control ERA virus, providing new insights in the biology of MALT1 and rabies virus infection.

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.

scholarly journals Changes in Fatty Acid Dietary Profile Affect the Brain–Gut Axis Functions of Healthy Young Adult Rats in a Sex-Dependent Manner

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1864
Author(s):  
Damian Jacenik ◽  
Ana Bagüés ◽  
Laura López-Gómez ◽  
Yolanda López-Tofiño ◽  
Amaia Iriondo-DeHond ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Young Adult ◽  
Standard Diet ◽  
Dependent Manner ◽  
Soy Oil ◽  
Evening Primrose ◽  
Brain Functions ◽  
Fa Composition ◽  
The Impact ◽  
The Brain

Dietary modifications, including those affecting dietary fat and its fatty acid (FA) composition, may be involved in the development of brain–gut axis disorders, with different manifestations in males and females. Our aim was to evaluate the impact of three purified diets with different FA composition on the brain–gut axis in rats of both sexes. Male and female Wistar rats fed a cereal-based standard diet from weaning were used. At young adult age (2–3 months old), animals were divided into three groups and treated each with a different refined diet for 6 weeks: a control group fed on AIN-93G diet containing 7% soy oil (SOY), and two groups fed on AIN-93G modified diets with 3.5% soy oil replaced by 3.5% coconut oil (COCO) or 3.5% evening primrose oil (EP). Different brain–gut axis parameters were evaluated during 4–6 weeks of dietary intervention. Compared with SOY diet (14% saturated FAs, and 58% polyunsaturated FAs), COCO diet (52.2% saturated FAs and 30% polyunsaturated FAs) produced no changes in brain functions and minor gastrointestinal modifications, whereas EP diet (11.1% saturated FAs and 70.56% polyunsaturated FAs) tended to decrease self-care behavior and colonic propulsion in males, and significantly increased exploratory behavior, accelerated gastrointestinal transit, and decreased cecum and fecal pellet density in females. Changes in FA composition, particularly an increase in ω-6 polyunsaturated FAs, seem to facilitate the development of brain–gut axis alterations in a sex-dependent manner, with a relatively higher risk in females.

scholarly journals Fatty Acid-Binding Protein 3 Expression in the Brain and Skin in Human Synucleinopathies

2021 ◽  
Vol 13 ◽  
Author(s):  
Hideki Oizumi ◽  
Kenshi Yamasaki ◽  
Hiroyoshi Suzuki ◽  
Takafumi Hasegawa ◽  
Yoko Sugimura ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Dopaminergic Neurons ◽  
Fatty Acid Binding Protein ◽  
Binding Protein ◽  
Amyloid Β ◽  
Human Tissues ◽  
Adult Onset ◽  
Fatty Acid Binding ◽  
Acid Binding Protein ◽  
The Brain

Parkinson’s disease (PD) and multiple system atrophy are types of adult-onset neurodegenerative disorders named synucleinopathies, which are characterized by prominent intracellular α-synuclein (αSyn) aggregates. We have previously found that αSyn aggregates and the vulnerability of dopaminergic neurons in the mouse brain are partly associated with the expression of fatty acid-binding protein 3 (FABP3, heart FABP). However, it remains to be elucidated whether FABP3 accumulation is associated with αSyn aggregates in human tissues. Here, we histologically studied FABP3 expression in human tissues obtained from patients with synucleinopathies, patients with Alzheimer disease (AD) and controls. We found that (1) a variety of neurons expressed the FABP3 protein in human brain tissues, (2) FABP3 was colocalized with αSyn aggregates in the brains of individuals with synucleinopathies but not with amyloid β or p-tau aggregates in the brains of individuals with AD, and (3) FABP3 was not present in p-αSyn deposits in biopsied skin tissues from individuals with PD. These findings suggest that FABP3 expression is associated with αSyn aggregation in synucleinopathies and provide new insights into the involvement of FABP3 in synucleinopathies.

scholarly journals The Protective Role of Sestrin2 in High Fat Diet-Induced Nephropathy

2020 ◽  
Author(s):  
Abdelali Agouni ◽  
Duck Y Lee ◽  
Assaad A Eid ◽  
Yves Gorin ◽  
Kumar Sharma
Keyword(s):  
Fatty Acid ◽  
Mouse Model ◽  
High Fat Diet ◽  
Chow Diet ◽  
Pathological Feature ◽  
Lipid Uptake ◽  
Wild Type ◽  
High Fat ◽  
Obesity And Diabetes ◽  
The Impact

Introduction: Obesity is a major risk factor for type-2 diabetes predisposing patients to diabetic nephropathy (DN), the leading cause of end-stage renal failure. Glomerular injury is a prominent pathological feature of DN. Sestrin2 (Sesn2) is a stress-induced protein, but its role in DN has not been investigated. Therefore, we have determined the impact of Sesn2 deletion in a mouse model of obesityinduced nephropathy. Materials and methods: We examined the effects of Sesn2-deficiency in a longterm (22 weeks) mouse model of high fat diet (HFD)-induced obesity on glomerular structure. The severity of renal injury and fibrosis in wild type (Sesn2+/+) mice (fed HFD or chow diets) was compared to that in Sesn2-deficient mice (Sesn2-/- ) fed HFD or chow diets. Animal work was carried out under an IACUC-approved protocol. Results: Data showed that Sesn2 ablation exacerbated HFD-induced glomerular fibrotic injury as evidenced by mesangial matrix hypertrophy and accumulation of both fibronectin and collagen IV. Western blot analysis revealed that HFD- or chow-fed Sesn2-/- mice exhibited higher protein expression of key lipogenic enzymes, fatty acid translocase CD36 (an indicator of lipid uptake), fatty acid synthase and ATP citrate lyase. Sesn2-deficiency in obese mice resulted in podocyte loss as indicated by reduced expression of synaptopodin. Glomerular lesions like those observed in HFD-fed wild-type mice were detected in Sesn2-/-mice fed a chow diet, indicating that the basal deletion of Sesn2 is deleterious by itself. Conclusions: We provide the first evidence that Sesn2 is renoprotective in obesity-induced nephropathy by diminishing lipid accumulation and blocking excessive lipid uptake and de novo lipid synthesis. Understanding the protective of Sesn2 should yield novel therapeutic interventions to effectively preserve glomerular function in obesity and diabetes.

scholarly journals Mathematical model shows how sleep may affect amyloid β fibrillization

2019 ◽  
Author(s):  
Masoud Hoore ◽  
Sahamoddin Khailaie ◽  
Ghazal Montaseri ◽  
Tanmay Mitra ◽  
Michael Meyer-Hermann
Keyword(s):  
Mathematical Model ◽  
Production Rate ◽  
Amyloid Β ◽  
Cellular Level ◽  
Long Time ◽  
Diseased State ◽  
Aβ Fibers ◽  
The Impact ◽  
The Brain ◽  
Good Sleep

AbstractDeposition of amyloid β (Aβ) fibers in extra-cellular matrix of the brain is a ubiquitous feature associated with several neurodegenerative disorders, especially Alzheimer’s disease (AD). While many of the biological aspects that contribute to the formation of Aβ plaques are well addressed at the intra- and inter-cellular level in short timescales, an understanding of how Aβ fibrillization usually starts to dominate at a longer timescale in spite of the presence of mechanisms dedicated to Aβ clearance, is still lacking. Furthermore, no existing mathematical model integrates the impact of diurnal neural activity as emanated from circadian regulation to predict disease progression due to a disruption in sleep-wake cycle. In this study, we develop a minimal model of Aβ fibrillization to investigate the onset of AD over a long time-scale. Our results suggest that the diseased state is a manifestation of a phase change of the system from soluble Aβ (sAβ) to fibrillar Aβ (fAβ) domination upon surpassing a threshold in the production rate of soluble Aβ. By incorporating the circadian rhythm into our model, we reveal that fAβ accumulation is crucially dependent on the regulation of sleep-wake cycle, thereby indicating the importance of a good sleep hygiene in averting AD onset. We also discuss potential intervention schemes to reduce fAβ accumulation in the brain by modification of the critical sAβ production rate.

scholarly journals Salivary Aβ Secretion and Altered Oral Microbiome in Mouse Models of AD

2021 ◽  
Vol 17 (12) ◽  
pp. 1133-1144
Author(s):  
Angela M. Floden ◽  
Mona Sohrabi ◽  
Suba Nookala ◽  
Jay J. Cao ◽  
Colin K. Combs
Keyword(s):  
Matched Control ◽  
Amyloid Β ◽  
Cell Types ◽  
Oral Microbiome ◽  
Aβ Peptide ◽  
Prior Work ◽  
Wild Type ◽  
Male And Female ◽  
Amyloid Aβ ◽  
The Brain

Background: Beta amyloid (Aβ) peptide containing plaque aggregations in the brain are a hallmark of Alzheimer’s Disease (AD). However, Aβ is produced by cell types outside of the brain suggesting that the peptide may serve a broad physiologic purpose. Objective: Based upon our prior work documenting expression of amyloid β precursor protein (APP) in intestinal epithelium we hypothesized that salivary epithelium might also express APP and be a source of Aβ. Methods: To begin testing this idea, we compared human age-matched control and AD salivary glands to C57BL/6 wild type, AppNL-G-F , and APP/PS1 mice. Results: Both male and female AD, AppNL-G-F , and APP/PS1 glands demonstrated robust APP and Aβ immunoreactivity. Female AppNL-G-F mice had significantly higher levels of pilocarpine stimulated Aβ 1-42 compared to both wild type and APP/PS1 mice. No differences in male salivary Aβ levels were detected. No significant differences in total pilocarpine stimulated saliva volumes were observed in any group. Both male and female AppNL-G-F but not APP/PS1 mice demonstrated significant differences in oral microbiome phylum and genus abundance compared to wild type mice. Male, but not female, APP/PS1 and AppNL-G-F mice had significantly thinner molar enamel compared to their wild type counterparts. Conclusion: These data support the idea that oral microbiome changes exist during AD in addition to changes in salivary Aβ and oral health.

Mechanistic Modeling of Soluble Aβ Dynamics and Target Engagement in the Brain by Anti-Aβ mAbs in Alzheimer’s Disease

2020 ◽  
Vol 17 (4) ◽  
pp. 393-406
Author(s):  
Gregory Z. Ferl ◽  
Reina N. Fuji ◽  
Jasvinder K. Atwal ◽  
Tony Sun ◽  
Saroja Ramanujan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Mechanistic Modeling ◽  
Model Parameters ◽  
Target Engagement ◽  
Binding Characteristics ◽  
The Impact ◽  
The Brain

Background: Anti-amyloid-β (Aβ) monoclonal antibodies (mAbs) are currently in development for treating Alzheimer’s disease. Objectives: To address the complexity of Aβ target engagement profiles, improve the understanding of crenezumab Pharmacokinetics (PK) and Aβ Pharmacodynamics (PD) in the brain, and facilitate comparison of anti-Aβ therapies with different binding characteristics. Methods: A mechanistic mathematical model was developed describing the distribution, elimination, and binding kinetics of anti-Aβ mAbs and Aβ (monomeric and oligomeric forms of Aβ1-40 and Aβ1-42) in the brain, Cerebrospinal Fluid (CSF), and plasma. Physiologically meaningful values were assigned to the model parameters based on the previous data, with remaining parameters fitted to clinical measurements of Aβ concentrations in CSF and plasma, and PK/PD data of patients undergoing anti-Aβ therapy. Aβ target engagement profiles were simulated using a Monte Carlo approach to explore the impact of biological uncertainty in the model parameters. Results: Model-based estimates of in vivo affinity of the antibody to monomeric Aβ were qualitatively consistent with the previous data. Simulations of Aβ target engagement profiles captured observed mean and variance of clinical PK/PD data. Conclusion: This model is useful for comparing target engagement profiles of different anti-Aβ therapies and demonstrates that 60 mg/kg crenezumab yields a significant increase in Aβ engagement compared with lower doses of solanezumab, supporting the selection of 60 mg/kg crenezumab for phase 3 studies. The model also provides evidence that the delivery of sufficient quantities of mAb to brain interstitial fluid is a limiting step with respect to the magnitude of soluble Aβ oligomer neutralization.

scholarly journals Dysregulated Gut Homeostasis Observed Prior to the Accumulation of the Brain Amyloid-β in Tg2576 Mice

2020 ◽  
Vol 21 (5) ◽  
pp. 1711 ◽  
Author(s):  
Pedram Honarpisheh ◽  
Caroline R. Reynolds ◽  
Maria P. Blasco Conesa ◽  
Jose F. Moruno Manchon ◽  
Nagireddy Putluri ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Tg2576 Mouse ◽  
Intestinal Epithelial ◽  
Gut Dysfunction ◽  
Gut Homeostasis ◽  
Plasma Cytokines ◽  
Aβ Aggregation ◽  
The Brain ◽  
Tg2576 Mice ◽  
Junction Proteins

Amyloid plaques in Alzheimer’s disease (AD) are associated with inflammation. Recent studies demonstrated the involvement of the gut in cerebral amyloid-beta (Aβ) pathogenesis; however, the mechanisms are still not well understood. We hypothesize that the gut bears the Aβ burden prior to brain, highlighting gut–brain axis (GBA) interaction in neurodegenerative disorders. We used pre-symptomatic (6-months) and symptomatic (15-months) Tg2576 mouse model of AD compared to their age-matched littermate WT control. We identified that dysfunction of intestinal epithelial barrier (IEB), dysregulation of absorption, and vascular Aβ deposition in the IEB occur before cerebral Aβ aggregation is detectible. These changes in the GBA were associated with elevated inflammatory plasma cytokines including IL-9, VEGF and IP-10. In association with reduced cerebral myelin tight junction proteins, we identified reduced levels of systemic vitamin B12 and decrease cubilin, an intestinal B12 transporter, after the development of cerebral Aβ pathology. Lastly, we report Aβ deposition in the intestinal autopsy from AD patients with confirmed cerebral Aβ pathology that is not present in intestine from non-AD controls. Our data provide evidence that gut dysfunction occurs in AD and may contribute to its etiology. Future therapeutic strategies to reverse AD pathology may involve the early manipulation of gut physiology and its microbiota.

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