Berberine Alleviates Amyloid-beta Pathogenesis Via Activating LKB1/AMPK Signaling in the Brain of APP/PS1 Transgenic Mice

2019 ◽  
Vol 19 (5) ◽  
pp. 342-348 ◽  
Author(s):  
Zhi-You Cai ◽  
Chuan-Ling Wang ◽  
Tao-Tao Lu ◽  
Wen-Ming Yang
Keyword(s):  
Transgenic Mice ◽  
Western Blotting ◽  
Amyloid Β ◽  
Adenosine Monophosphate ◽  
Camp Response Element Binding ◽  
Enzyme Linked Immunosorbent Assay ◽  
Synaptic Density ◽  
Ampk Signaling ◽  
The Brain ◽  
Post Synaptic Density

Background:Liver kinase B1 (LKB1)/5’-adenosine monophosphate-activated protein kinase (AMPK) signaling, a metabolic checkpoint, plays a neuro-protective role in the pathogenesis of Alzheimer’s disease (AD). Amyloid-β (Aβ) acts as a classical biomarker of AD. The aim of the present study was to explore whether berberine (BBR) activates LKB1/AMPK signaling and ameliorates Aβ pathology.Methods:The Aβ levels were detected using enzyme-linked immunosorbent assay and immunohistochemistry. The following biomarkers were measured by Western blotting: phosphorylated (p-) LKB1 (Ser334 and Thr189), p-AMPK (AMPKα and AMPKβ1), synaptophysin, post-synaptic density protein 95 and p-cAMP-response element binding protein (p-CREB). The glial fibrillary acidic protein (GFAP) was determined using Western blotting and immunohistochemistry.Results:BBR inhibited Aβ expression in the brain of APP/PS1 mice. There was a strong up-regulation of both p-LKB1 (Ser334 and Thr189) and p-AMPK (AMPKα and AMPKβ1) in the brains of APP/PS1 transgenic mice after BBR-treatment (P<0.01). BBR promoted the expression of synaptophysin, post-synaptic density protein 95 and p-CREB(Ser133) in the AD brain, compared with the model mice.Conclusion:BBR alleviates Aβ pathogenesis and rescues synapse damage via activating LKB1/AMPK signaling in the brain of APP/PS1 transgenic mice.

scholarly journals CYP46A1-dependent and independent effects of efavirenz treatment

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Natalia Mast ◽  
Nicole El-Darzi ◽  
Alexey M Petrov ◽  
Young Li ◽  
Irina A Pikuleva
Keyword(s):  
Cytochrome P450 ◽  
Steroid Hormones ◽  
Small Dose ◽  
Amyloid Β ◽  
Enzyme Activation ◽  
Synaptic Function ◽  
Synaptic Density ◽  
5Xfad Mice ◽  
The Brain ◽  
Post Synaptic Density

Abstract Cholesterol excess in the brain is mainly disposed via cholesterol 24-hydroxylation catalysed by cytochrome P450 46A1, a CNS-specific enzyme. Cytochrome P450 46A1 is emerging as a promising therapeutic target for various brain diseases with both enzyme activation and inhibition having therapeutic potential. The rate of cholesterol 24-hydroxylation determines the rate of brain cholesterol turnover and the rate of sterol flux through the plasma membranes. The latter was shown to affect membrane properties and thereby membrane proteins and membrane-dependent processes. Previously we found that treatment of 5XFAD mice, an Alzheimer’s disease model, with a small dose of anti-HIV drug efavirenz allosterically activated cytochrome P450 46A1 in the brain and mitigated several disease manifestations. Herein, we generated Cyp46a1−/−5XFAD mice and treated them, along with 5XFAD animals, with efavirenz to ascertain cytochrome P450 46A1-dependent and independent drug effects. Efavirenz-treated versus control Cyp46a1−/−5XFAD and 5XFAD mice were compared for the brain sterol and steroid hormone content, amyloid β burden, protein and mRNA expression as well as synaptic ultrastructure. We found that the cytochrome P450 46A1-dependent efavirenz effects included changes in the levels of brain sterols, steroid hormones, and such proteins as glial fibrillary acidic protein, Iba1, Munc13-1, post-synaptic density-95, gephyrin, synaptophysin and synapsin-1. Changes in the expression of genes involved in neuroprotection, neurogenesis, synaptic function, inflammation, oxidative stress and apoptosis were also cytochrome P450 46A1-dependent. The total amyloid β load was the same in all groups of animals, except lack of cytochrome P450 46A1 decreased the production of the amyloid β40 species independent of treatment. In contrast, altered transcription of genes from cholinergic, monoaminergic, and peptidergic neurotransmission, steroid sulfation and production as well as vitamin D3 activation was the main CYP46A1-independent efavirenz effect. Collectively, the data obtained reveal that CYP46A1 controls cholesterol availability for the production of steroid hormones in the brain and the levels of biologically active neurosteroids. In addition, cytochrome P450 46A1 activity also seems to affect the levels of post-synaptic density-95, the main postsynaptic density protein, possibly by altering the calcium/calmodulin-dependent protein kinase II inhibitor 1 expression and activity of glycogen synthase kinase 3β. Even at a small dose, efavirenz likely acts as a transcriptional regulator, yet this regulation may not necessarily lead to functional effects. This study further confirmed that cytochrome P450 46A1 is a key enzyme for cholesterol homeostasis in the brain and that the therapeutic efavirenz effects on 5XFAD mice are likely realized via cytochrome P450 46A1 activation.

scholarly journals LongShengZhi Capsule Attenuates Alzheimer-Like Pathology in APP/PS1 Double Transgenic Mice by Reducing Neuronal Oxidative Stress and Inflammation

2020 ◽  
Vol 12 ◽  
Author(s):  
Zequn Yin ◽  
Xuerui Wang ◽  
Shihong Zheng ◽  
Peichang Cao ◽  
Yuanli Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transgenic Mice ◽  
Amyloid Β ◽  
B Cell Lymphoma ◽  
Acanthopanax Senticosus ◽  
Neuroprotective Effects ◽  
Long Term Treatment ◽  
Double Transgenic Mice ◽  
The Brain

Alzheimer’s disease (AD) is the most common form of dementia in the elderly. It may be caused by oxidative stress, inflammation, and cerebrovascular dysfunctions in the brain. LongShengZhi Capsule (LSZ), a traditional Chinese medicine, has been approved by the China Food and Drug Administration for treatment of patients with cardiovascular/cerebrovascular disease. LSZ contains several neuroprotective ingredients, including Hirudo, Astmgali Radix, Carthami Flos (Honghua), Persicae Semen (Taoren), Acori Tatarinowii Rhizoma (Shichangpu), and Acanthopanax Senticosus (Ciwujia). In this study, we aimed to determine the effect of LSZ on the AD process. Double transgenic mice expressing the amyloid-β precursor protein and mutant human presenilin 1 (APP/PS1) to model AD were treated with LSZ for 7 months starting at 2 months of age. LSZ significantly improved the cognition of the mice without adverse effects, indicating its high degree of safety and efficacy after a long-term treatment. LSZ reduced AD biomarker Aβ plaque accumulation by inhibiting β-secretase and γ-secretase gene expression. LSZ also reduced p-Tau expression, cell death, and inflammation in the brain. Consistently, in vitro, LSZ ethanol extract enhanced neuronal viability by reducing L-glutamic acid-induced oxidative stress and inflammation in HT-22 cells. LSZ exerted antioxidative effects by enhancing superoxide dismutase and glutathione peroxidase expression, reduced Aβ accumulation by inhibiting β-secretase and γ-secretase mRNA expression, and decreased p-Tau level by inhibiting NF-κB-mediated inflammation. It also demonstrated neuroprotective effects by regulating the Fas cell surface death receptor/B-cell lymphoma 2/p53 pathway. Taken together, our study demonstrates the antioxidative stress, anti-inflammatory, and neuroprotective effects of LSZ in the AD-like pathological process and suggests it could be a potential medicine for AD treatment.

Berberine Alleviates Amyloid-Beta Pathology in the Brain of APP/PS1 Transgenic Mice via Inhibiting β/γ-Secretases Activity and Enhancing α-Secretases

2018 ◽  
Vol 15 (11) ◽  
pp. 1045-1052 ◽  
Author(s):  
Zhiyou Cai ◽  
Chuanling Wang ◽  
Wenbo He ◽  
Yi Chen
Keyword(s):  
Western Blotting ◽  
Amyloid Beta ◽  
Water Maze ◽  
Senile Plaque ◽  
Memory Deficits ◽  
Brain Diseases ◽  
Enzyme Linked Immunosorbent Assay ◽  
Neuroprotective Effects ◽  
Improved Learning ◽  
The Brain

Background: Berberine (BBR) has neuroprotective effects on many brain diseases, including Alzheimer’s disease (AD). Amyloid -beta (Aβ) senile plaque is the most classical pathological hallmarks of AD. Aβ produces from a sequential cleavage by β-secretase (beta-site amyloid precursor protein cleaving enzyme 1, BACE1) and γ -secretase. The aim of our work was to investigate whether the neuroprotective effects of BBR on AD is related to inhibiting Aβ pathology. Method: The cognitive function of mice was assessed by the Morris water maze (MWM) test. The Aβ levels were determined by enzyme linked immunosorbent assay; the expression of APP, sAPPα, ADAM10 and ADAM17, sAPPβ and BACE1 was detected by Western blotting; and the activity of γ -secretase complex (NCT, PS1, Aph-1α and Pen-2) was determined by Western blotting and immunohistochemistry. Results: BBR improved learning and memory deficits of APP/PS1 mice. BBR decreased Aβ levels in the hippocampus of APP/PS1 mice. BACE1 and sAPP -β levels in the BBR-treated groups were significantly reduced in the hippocampus of AD mice. BBR markedly decreased the expression of PS1, Aph-1α and Pen-2, but had no effect on NCT. The levels of sAPPα, ADAM10 and ADAM17 in the hippocampus of BBR-treated mice significantly increased, compared with the control ones (P<0.05). Conclusion: BBR inhibits the activity of β/γ-secretases, enhances α-secretases, and lowers the Aβ level in the hippocampus of AD mice, and improves Alzheimer’s-like cognitive impairment.

Localization of fused in sarcoma (FUS) protein to the post-synaptic density in the brain

2012 ◽  
Vol 124 (3) ◽  
pp. 383-394 ◽  
Author(s):  
Naoya Aoki ◽  
Shinji Higashi ◽  
Ito Kawakami ◽  
Zen Kobayashi ◽  
Masato Hosokawa ◽  
...  
Keyword(s):  
Synaptic Density ◽  
Fused In Sarcoma ◽  
The Brain ◽  
Post Synaptic Density ◽  
Fus Protein

scholarly journals Effect of Electro-Acupuncture at ST36 and SP6 on the cAMP -CREB Pathway and mRNA Expression Profile in the Brainstem of Morphine Tolerant Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Qisheng Wang ◽  
Fenfen Qin ◽  
Hui Wang ◽  
Huanya Yang ◽  
Qingyang Liu ◽  
...  
Keyword(s):  
Antinociceptive Effect ◽  
Cyclic Adenosine Monophosphate ◽  
Fold Increase ◽  
Adenosine Monophosphate ◽  
Repeated Administration ◽  
Underlying Mechanism ◽  
Camp Response Element Binding ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tail Flick ◽  
Hot Plate Test

Undoubtedly, opioid drugs have been the most popular treatment for refractory pain since found, such as morphine. However, tolerance to the analgesic effects caused by repeated use is inevitable, which greatly limits the clinical application of these drugs. Nowadays, it has become the focus of the world that further development of non-opioid-based treatment along with efficient strategies to circumvent opioid tolerance are urgently needed clinically. Fortunately, electro-acupuncture (EA) provides an alternative to pharmaceutic treatment, remaining its potential mechanisms unclear although. This study was aimed to observe the effects of EA on morphine-induced tolerance in mice and discover its underlying mechanism. Tail-flick assay and hot-plate test were conducted to assess the development of tolerance to morphine-induced analgesia effect. As a result of repeated administration scheme (10 mg/kg, twice per day, for 7 days), approximately a two-fold increase was observed in the effective dose of 50% (ED50) of morphine-induced antinociceptive effect. Interestingly, by EA treatment (2/100Hz, 0.5, 1.0, and 1.5 mA, 30 min/day for 7 days) at the acupoints Zusanli (ST36) and Sanyinjiao (SP6), morphine ED50 curves was remarkably leftward shifted on day 8. In addition, the RNA sequencing strategy was used to reveal the potential mechanisms. Due to the well described relevance of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), extracellular regulated protein kinases (ERK), and cAMP response element-binding (CREB) in brainstem (BS) to analgesia tolerance, the cAMP-PKA/ERK-CREB signaling was deeply concerned in this study. Based upon Enzyme-Linked Immunosorbent Assay, the up-regulation of the cAMP level was observed, whereas reversed with EA treatment. Similarly, western blot revealed the phosphorylation levels of PKA, ERK, and CREB were up-regulated in morphine tolerant mice, whereas the EA group showed a significantly reduced expression level instead. This study observed an attenuating effect of the EA at ST36 and SP6 on morphine tolerance in mice, and suggested several potential biological targets by RNA-seq, which include the cAMP-PKA/ERK-CREB signaling pathway, strongly supporting a useful treatment for combatting the opioid epidemic, and opioid-tolerant patients.

scholarly journals Early-onset and Robust Cerebral Microvascular Accumulation of Amyloid β-Protein in Transgenic Mice Expressing Low Levels of a Vasculotropic Dutch/Iowa Mutant Form of Amyloid β-Protein Precursor

2004 ◽  
Vol 279 (19) ◽  
pp. 20296-20306 ◽  
Author(s):  
Judianne Davis ◽  
Feng Xu ◽  
Rashid Deane ◽  
Galina Romanov ◽  
Mary Lou Previti ◽  
...  
Keyword(s):  
Early Onset ◽  
Amyloid Β ◽  
Enzyme Linked Immunosorbent Assay ◽  
Mutant Form ◽  
Amyloid Β Protein ◽  
Pathological Feature ◽  
High Association ◽  
Cerebral Microvessels ◽  
Β Protein ◽  
The Brain

Cerebrovascular deposition of amyloid β-protein (Aβ) is a common pathological feature of Alzheimer's disease and related disorders. In particular, the Dutch E22Q and Iowa D23N mutations in Aβ cause familial cerebrovascular amyloidosis with abundant diffuse amyloid plaque deposits. Both of these charge-altering mutations enhance the fibrillogenic and pathogenic properties of Aβin vitro. Here, we describe the generation of several transgenic mouse lines (Tg-SwDI) expressing human neuronal Aβ precursor protein (AβPP) harboring the Swedish K670N/M671L and vasculotropic Dutch/Iowa E693Q/D694N mutations under the control of the mouse Thy1.2 promoter. Tg-SwDI mice expressed transgenic human AβPP only in the brain, but at levels below those of endogenous mouse AβPP. Despite the paucity of human AβPP expression, quantitative enzyme-linked immunosorbent assay measurements revealed that Tg-SwDI mice developed early-onset and robust accumulation of Aβ in the brain with high association with isolated cerebral microvessels. Tg-SwDI mice exhibited striking perivascular/vascular Aβ deposits that markedly increased with age. The vascular Aβ accumulations were fibrillar, exhibiting strong thioflavin S staining, and occasionally presented signs of microhemorrhage. In addition, numerous largely diffuse, plaque-like structures were observed starting at 3 months of age.In vivotransport studies demonstrated that Dutch/Iowa mutant Aβ was more readily retained in the brain compared with wild-type Aβ. These results with Tg-SwDI mice demonstrate that overexpression of human AβPP is not required for early-onset and robust accumulation of both vascular and parenchymal Aβ in mouse brain.

scholarly journals Quinacrine directly dissociates amyloid plaques in the brain of 5XFAD transgenic mouse model of Alzheimer’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sohui Park ◽  
Hye Yun Kim ◽  
Hyun-A Oh ◽  
Jisu Shin ◽  
In Wook Park ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Weight ◽  
Transgenic Mice ◽  
Cortical Neurons ◽  
Amyloid Β ◽  
Synaptic Function ◽  
Western Blots ◽  
Aβ Fibrils ◽  
The Brain

AbstractAlzheimer’s disease (AD) is the most common type of dementia characterized by the abnormal accumulation of amyloid-β (Aβ) in the brain. Aβ misfolding is associated with neuroinflammation and synaptic dysfunction, leading to learning and memory deficits. Therefore, Aβ production and aggregation have been one of the most popular drug targets for AD. Failures of drug candidates regulating the aforementioned Aβ cascade stimulated development of immunotherapy agents for clearance of accumulated Aβ in the brain. Here, we report that quinacrine, a blood–brain barrier penetrating antimalarial chemical drug, dissociates Aβ plaques in the brain of AD transgenic mice. When co-incubated with pre-formed Aβ fibrils, quinacrine decreased thioflavin T-positive β-sheets in vitro, on top of its inhibitory function on the fibril formation. We confirmed that quinacrine induced dissociation of high-molecular-weight Aβ aggregates into low-molecular-weight species by dot blots in association with size cut-off filtrations. Quinacrine was then administered to adult 5XFAD transgenic mice via weekly intravenous injections for 6 weeks, and we found a significant reduction of Aβ plaques and astrocytosis in their cortex and hippocampus. In western blots of quinacrine-administered mouse brains, amelioration of AD-related biomarkers, glial fibrillary acidic protein, postsynaptic protein 95, phosphorylated cAMP response element-binding protein, phosphorylated c-Jun N-terminal kinase were observed. Lastly, quinacrine-stimulated dissociation of misfolded aggregates induced recovery of synaptic function associated with Aβ in excitatory post-synaptic current recordings of primary rat cortical neurons treated with Aβ aggregates and quinacrine. Collectively, quinacrine can directly dissociate Aβ fibrils and alleviate decreased synaptic functions.

scholarly journals Eriodictyol ameliorated cognitive dysfunction in APP/PS1 mice through inhibited ferroptosis via vitamin D receptor mediated Nrf2 activation

2021 ◽  
Author(s):  
Lin Li ◽  
Wenjun Li ◽  
Xiangru Zheng ◽  
Qinglong Liu ◽  
Qian Du ◽  
...  
Keyword(s):  
Vitamin D ◽  
Signaling Pathway ◽  
Western Blotting ◽  
Vitamin D Receptor ◽  
Amyloid Β ◽  
Qpcr Assay ◽  
Aβ Aggregation ◽  
The Brain

Abstract Background Alzheimer's disease (AD) is the most common type of neurodegenerative disease in contemporary era, and it is still clinically incurable. Eriodictyol, a natural flavonoid compound mainly exists in citrus fruits and some Chinese herbal medicine, has been reported with its effect of anti-inflammatory, antioxidant, anti-cancer and neuroprotective effects. However, there are few studies on the anti-AD effect and molecular mechanism of eriodictyol. Methods APP/PS1 mice were treated with eriodictyol and the cognitive function of mice was assessed by behavioral tests. The level of amyloid-β (Aβ) aggregation and hyper-phosphorylation of Tau in the brain of mice were detected by histological analysis and Western blotting. Meanwhile, HT-22 cells which induced by amyloid-β peptide (1-42) (Aβ1−42) oligomer were treated with eriodictyol after which cell viability was determined and the production of p-Tau was tested by Western blotting. Then, the characteristics of ferroptosis, including iron aggregation, lipid peroxidation and the expression of glutathione peroxidase type 4(GPX4), were determined both in vivo and in vitro by Fe straining, Western blotting and qPCR assay. Additionally, the expression level of Vitamin D receptor (VDR) and the activity of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway were tested by Western blotting and qPCR assay. After that, the HT-22 cells with VDR knockout were used to explore the potential mechanisms and the relationship between VDR and Nrf2 was further assessed by coimmunoprecipitation assay and bioinformatics analysis. Results Eriodictyol obviously ameliorated cognitive deficits in APP/PS1 mice, suppressed Aβ aggregation and the phosphorylated level Tau in the brain of APP/PS1 mice. Meanwhile, eriodictyol could inhibit Tau hyper-phosphorylation and neurotoxicity in HT-22 cells induced by Aβ1−42 oligomer. Furthermore, both in vivo and in vitro, eriodictyol showed the anti-ferroptosis effect and its mechanism may connected with the activation of Nrf2/HO-1 signaling pathway. Additionally, the further experiment explains that the activation of Nrf2/HO-1 signaling pathway with eriodictyol treatment mediated by VDR. Conclusions Eriodictyol alleviated memory impairment and AD-like pathological changes via activating Nrf2/HO-1 signaling pathway mediated by VDR, which provide a new possibility for the treatment of AD.

scholarly journals Low-Dose Phosphodiesterase III Inhibitor Reduces the Vascular Amyloid Burden in Amyloid-β Protein Precursor Transgenic Mice

2020 ◽  
Vol 21 (7) ◽  
pp. 2295 ◽  
Author(s):  
Yusuke Yakushiji ◽  
Kazuhiro Kawamoto ◽  
Kazuyoshi Uchihashi ◽  
Masafumi Ihara ◽  
Shigehisa Aoki ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Senile Plaque ◽  
Amyloid Β ◽  
Control Group ◽  
Amyloid Angiopathy ◽  
Amyloid Β Protein ◽  
Amyloid Burden ◽  
Phosphodiesterase Iii Inhibitor ◽  
The Brain ◽  
Aspirin Group

A previous study reported that relatively high-dose cilostazol (0.3%) promoted the drainage of cerebrovascular amyloid-β (Aβ) protein in Aβ Precursor Protein (APP) transgenic mice overexpressing vasculotropic Aβ. We investigated whether lower-dose cilostazol can decrease micro-hemorrhages and Aβ deposition in the brain using APP transgenic mice. At baseline, 14-month-old female Tg2576 mice were randomly assigned to a control group (vehicle), aspirin group (0.01% aspirin), or cilostazol group (0.01% cilostazol). The severity of cerebral micro-hemorrhages (i.e., number), area of senile plaque, and severity of vascular amyloid burden (quantified with cerebral amyloid angiopathy (CAA) score (=number of Aβ-positive vessels × severity of amyloid burden of Aβ-positive vessels) were evaluated in the brain of mice aged 15 and 21–23 months. At 15 months, no differences were shown in each pathological change among the three groups. At 21–23 months, there were no differences in the severity of cerebral micro-hemorrhages or area of senile plaque among the three groups. However, the CAA score was significantly lower in the cilostazol compared to the control group (p = 0.046, Mann–Whitney U test), although no difference was seen between the control and aspirin group. Our study showed that lower-dose cilostazol could reduce the vascular amyloid burden without increasing cerebral micro-hemorrhages in APP transgenic mice.

scholarly journals Chronic Exposure to High Altitude: Synaptic, Astroglial and Memory Changes

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Rupali Sharma ◽  
Nathan P. Cramer ◽  
Bayley Perry ◽  
Zahra Adahman ◽  
Erin K. Murphy ◽  
...  
Keyword(s):  
High Altitude ◽  
Chronic Exposure ◽  
Synaptic Proteins ◽  
Synaptic Density ◽  
Protein Levels ◽  
New Findings ◽  
Health Complications ◽  
The Brain ◽  
Post Synaptic Density

Abstract Long-term operations carried out at high altitude (HA) by military personnel, pilots, and astronauts may trigger health complications. In particular, chronic exposure to high altitude (CEHA) has been associated with deficits in cognitive function. In this study, we found that mice exposed to chronic HA (5000 m for 12 weeks) exhibited deficits in learning and memory associated with hippocampal function and were linked with changes in the expression of synaptic proteins across various regions of the brain. Specifically, we found decreased levels of synaptophysin (SYP) (p < 0.05) and spinophilin (SPH) (p < 0.05) in the olfactory cortex, post synaptic density−95 (PSD-95) (p < 0.05), growth associated protein 43 (GAP43) (p < 0.05), glial fibrillary acidic protein (GFAP) (p < 0.05) in the cerebellum, and SYP (p < 0.05) and PSD-95 (p < 0.05) in the brainstem. Ultrastructural analyses of synaptic density and morphology in the hippocampus did not reveal any differences in CEHA mice compared to SL mice. Our data are novel and suggest that CEHA exposure leads to cognitive impairment in conjunction with neuroanatomically-based molecular changes in synaptic protein levels and astroglial cell marker in a region specific manner. We hypothesize that these new findings are part of highly complex molecular and neuroplasticity mechanisms underlying neuroadaptation response that occurs in brains when chronically exposed to HA.

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