Caffeoylquinic Acids in Centella asiatica Reverse Cognitive Deficits in Male 5XFAD Alzheimer’s Disease Model Mice

Centella asiatica (CA) is an edible plant and a popular botanical dietary supplement. It is reputed, in Ayurveda, to mitigate age-related cognitive decline. There is a considerable body of preclinical literature supporting CA’s ability to improve learning and memory. This study evaluated the contribution of CA’s triterpenes (TT), widely considered its active compounds, and caffeoylquinic acids (CQA) to the cognitive effects of CA water extract (CAW) in 5XFAD mice, a model of Alzheimer’s disease. 5XFAD mice were fed a control diet alone, or one containing 1% CAW or compound groups (TT, CQA, or TT + CQA) equivalent to their content in 1% CAW. Wild-type (WT) littermates received the control diet. Conditioned fear response (CFR) was evaluated after 4.5 weeks. Female 5XFAD controls showed no deficit in CFR compared to WT females, nor any effects from treatment. In males, CFR of 5XFAD controls was attenuated compared to WT littermates (p = 0.005). 5XFAD males receiving CQA or TT + CQA had significantly improved CFR (p < 0.05) compared to 5XFAD male controls. CFR did not differ between 5XFAD males receiving treatment diets and WT males. These data confirm a role for CQA in CAW’s cognitive effects.

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Centella asiatica Alters Metabolic Pathways Associated With Alzheimer’s Disease in the 5xFAD Mouse Model of ß-Amyloid Accumulation

Frontiers in Pharmacology ◽

10.3389/fphar.2021.788312 ◽

2021 ◽

Vol 12 ◽

Author(s):

Alex B. Speers ◽

Manuel García-Jaramillo ◽

Alicia Feryn ◽

Donald G. Matthews ◽

Talia Lichtenberg ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Metabolic Pathways ◽

Centella Asiatica ◽

Metabolomic Analysis ◽

Wild Type ◽

Amyloid Accumulation ◽

5Xfad Mouse ◽

5Xfad Mice ◽

The Brain

Centella asiatica is an herb used in Ayurvedic and traditional Chinese medicine for its beneficial effects on brain health and cognition. Our group has previously shown that a water extract of Centella asiatica (CAW) elicits cognitive-enhancing effects in animal models of aging and Alzheimer’s disease, including a dose-related effect of CAW on memory in the 5xFAD mouse model of ß-amyloid accumulation. Here, we endeavor to elucidate the mechanisms underlying the effects of CAW in the brain by conducting a metabolomic analysis of cortical tissue from 5xFAD mice treated with increasing concentrations of CAW. Tissue was collected from 8-month-old male and female 5xFAD mice and their wild-type littermates treated with CAW (0, 200, 500, or 1,000 mg/kg/d) dissolved in their drinking water for 5 weeks. High-performance liquid chromatography coupled to high-resolution mass spectrometry analysis was performed and relative levels of 120 annotated metabolites were assessed in the treatment groups. Metabolomic analysis revealed sex differences in the effect of the 5xFAD genotype on metabolite levels compared to wild-type mice, and variations in the metabolomic response to CAW depending on sex, genotype, and CAW dose. In at least three of the four treated groups (5xFAD or wild-type, male or female), CAW (500 mg/kg/d) significantly altered metabolic pathways related to purine metabolism, nicotinate and nicotinamide metabolism, and glycerophospholipid metabolism. The results are in line with some of our previous findings regarding specific mechanisms of action of CAW (e.g., improving mitochondrial function, reducing oxidative stress, and increasing synaptic density). Furthermore, these findings provide new information about additional, potential mechanisms for the cognitive-enhancing effect of CAW, including upregulation of nicotinamide adenine dinucleotide in the brain and modulation of brain-derived neurotrophic factor. These metabolic pathways have been implicated in the pathophysiology of Alzheimer’s disease, highlighting the therapeutic potential of CAW in this neurodegenerative disease.

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Prolonged Treatment with Centella asiatica Improves Memory, Reduces Amyloid-β Pathology, and Activates NRF2-Regulated Antioxidant Response Pathway in 5xFAD Mice

Journal of Alzheimer s Disease ◽

10.3233/jad-210271 ◽

2021 ◽

pp. 1-16

Author(s):

Jonathan A. Zweig ◽

Mikah S. Brandes ◽

Barbara H. Brumbach ◽

Maya Caruso ◽

Kirsten M. Wright ◽

...

Keyword(s):

Gene Expression ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Plasticity ◽

Amyloid Β ◽

Centella Asiatica ◽

Antioxidant Response ◽

Prolonged Treatment ◽

Plaque Burden ◽

5Xfad Mice

Background: The medicinal herb Centella asiatica has been long been used for its neuroprotective and cognitive enhancing effects. We have previously shown that two weeks of treatment with a water extract of Centella asiatica (CAW) improves cognition and activates the endogenous antioxidant response pathway without altering amyloid-β (Aβ) plaque burden. Objective: Here, we assess the effect of long-term treatment of CAW in the 5xFAD mouse model of Aβ accumulation. Methods: Four-month-old 5xFAD mice were treated with CAW in their drinking water (2 g/L) for three months at which point they underwent cognitive testing as well as analysis of Aβ plaque levels and antioxidant and synaptic gene expression. In order to confirm the involvement of the antioxidant regulatory transcription factor NRF2 on the effects of CAW on synaptic plasticity, neurons isolated from 5xFAD mice were also treated with CAW and the targeted inhibitor ML385. Results: Three months of treatment with CAW improved spatial and contextual memory as well as executive function in 5xFAD mice. This improvement was accompanied by increased antioxidant gene expression and a decrease in Aβ plaque burden relative to untreated 5xFAD animals. In isolated neurons, treatment with ML385 blocked the effects of CAW on dendritic arborization and synaptic gene expression. Conclusion: These results suggest that prolonged CAW exposure could be beneficial in Alzheimer’s disease and that these effects likely involve NRF2 activation. Moreover, these findings suggest that targeting NRF2 itself may be a relevant therapeutic strategy for improving synaptic plasticity and cognitive function in Alzheimer’s disease.

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In vivo multi-parametric manganese-enhanced MRI for detecting amyloid plaques in rodent models of Alzheimer’s disease

Scientific Reports ◽

10.1038/s41598-021-91899-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Eugene Kim ◽

Davide Di Censo ◽

Mattia Baraldo ◽

Camilla Simmons ◽

Ilaria Rosa ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Plaques ◽

Transgenic Animals ◽

Surrounding Tissue ◽

Rodent Models ◽

Enhanced Mri ◽

5Xfad Mice ◽

Manganese Enhanced Mri

AbstractAmyloid plaques are a hallmark of Alzheimer’s disease (AD) that develop in its earliest stages. Thus, non-invasive detection of these plaques would be invaluable for diagnosis and the development and monitoring of treatments, but this remains a challenge due to their small size. Here, we investigated the utility of manganese-enhanced MRI (MEMRI) for visualizing plaques in transgenic rodent models of AD across two species: 5xFAD mice and TgF344-AD rats. Animals were given subcutaneous injections of MnCl2 and imaged in vivo using a 9.4 T Bruker scanner. MnCl2 improved signal-to-noise ratio but was not necessary to detect plaques in high-resolution images. Plaques were visible in all transgenic animals and no wild-types, and quantitative susceptibility mapping showed that they were more paramagnetic than the surrounding tissue. This, combined with beta-amyloid and iron staining, indicate that plaque MR visibility in both animal models was driven by plaque size and iron load. Longitudinal relaxation rate mapping revealed increased manganese uptake in brain regions of high plaque burden in transgenic animals compared to their wild-type littermates. This was limited to the rhinencephalon in the TgF344-AD rats, while it was most significantly increased in the cortex of the 5xFAD mice. Alizarin Red staining suggests that manganese bound to plaques in 5xFAD mice but not in TgF344-AD rats. Multi-parametric MEMRI is a simple, viable method for detecting amyloid plaques in rodent models of AD. Manganese-induced signal enhancement can enable higher-resolution imaging, which is key to visualizing these small amyloid deposits. We also present the first in vivo evidence of manganese as a potential targeted contrast agent for imaging plaques in the 5xFAD model of AD.

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Pharmacological ablation of astrocytes reduces Aβ degradation and synaptic connectivity in an ex vivo model of Alzheimer’s disease

Journal of Neuroinflammation ◽

10.1186/s12974-021-02117-y ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Nicola Davis ◽

Bibiana C. Mota ◽

Larissa Stead ◽

Emily O. C. Palmer ◽

Laura Lombardero ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Culture Media ◽

Ex Vivo ◽

Wild Type ◽

Insulin Degrading Enzyme ◽

Ex Vivo Model ◽

Model Of Alzheimer’S Disease ◽

Aβ Clearance ◽

5Xfad Mice

Abstract Background Astrocytes provide a vital support to neurons in normal and pathological conditions. In Alzheimer’s disease (AD) brains, reactive astrocytes have been found surrounding amyloid plaques, forming an astrocytic scar. However, their role and potential mechanisms whereby they affect neuroinflammation, amyloid pathology, and synaptic density in AD remain unclear. Methods To explore the role of astrocytes on Aβ pathology and neuroinflammatory markers, we pharmacologically ablated them in organotypic brain culture slices (OBCSs) from 5XFAD mouse model of AD and wild-type (WT) littermates with the selective astrocytic toxin L-alpha-aminoadipate (L-AAA). To examine the effects on synaptic circuitry, we measured dendritic spine number and size in OBCSs from Thy-1-GFP transgenic mice incubated with synthetic Aβ42 or double transgenics Thy-1-GFP/5XFAD mice treated with LAAA or vehicle for 24 h. Results Treatment of OBCSs with L-AAA resulted in an increased expression of pro-inflammatory cytokine IL-6 in conditioned media of WTs and 5XFAD slices, associated with changes in microglia morphology but not in density. The profile of inflammatory markers following astrocytic loss was different in WT and transgenic cultures, showing reductions in inflammatory mediators produced in astrocytes only in WT sections. In addition, pharmacological ablation of astrocytes led to an increase in Aβ levels in homogenates of OBCS from 5XFAD mice compared with vehicle controls, with reduced enzymatic degradation of Aβ due to lower neprilysin and insulin-degrading enzyme (IDE) expression. Furthermore, OBSCs from wild-type mice treated with L-AAA and synthetic amyloid presented 56% higher levels of Aβ in culture media compared to sections treated with Aβ alone, concomitant with reduced expression of IDE in culture medium, suggesting that astrocytes contribute to Aβ clearance and degradation. Quantification of hippocampal dendritic spines revealed a reduction in their density following L-AAA treatment in all groups analyzed. In addition, pharmacological ablation of astrocytes resulted in a decrease in spine size in 5XFAD OBCSs but not in OBCSs from WT treated with synthetic Aβ compared to vehicle control. Conclusions Astrocytes play a protective role in AD by aiding Aβ clearance and supporting synaptic plasticity.

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Cognitive Effects of Aerobic Exercise in Alzheimer’s Disease: A Pilot Randomized Controlled Trial

Journal of Alzheimer s Disease ◽

10.3233/jad-201100 ◽

2021 ◽

pp. 1-12

Author(s):

Fang Yu ◽

David M. Vock ◽

Lin Zhang ◽

Dereck Salisbury ◽

Nathaniel W. Nelson ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Randomized Controlled Trial ◽

Aerobic Exercise ◽

Controlled Trial ◽

Moderate Intensity ◽

Cognitive Effects ◽

Data Set ◽

Randomized Controlled

Background: Aerobic exercise has shown inconsistent cognitive effects in older adults with Alzheimer’s disease (AD) dementia. Objective: To examine the immediate and longitudinal effects of 6-month cycling on cognition in older adults with AD dementia. Methods: This randomized controlled trial randomized 96 participants (64 to cycling and 32 to stretching for six months) and followed them for another six months. The intervention was supervised, moderate-intensity cycling for 20–50 minutes, 3 times a week for six months. The control was light-intensity stretching. Cognition was assessed at baseline, 3, 6, 9, and 12 months using the AD Assessment Scale-Cognition (ADAS-Cog). Discrete cognitive domains were measured using the AD Uniform Data Set battery. Results: The participants were 77.4±6.8 years old with 15.6±2.9 years of education, and 55%were male. The 6-month change in ADAS-Cog was 1.0±4.6 (cycling) and 0.1±4.1 (stretching), which were both significantly less than the natural 3.2±6.3-point increase observed naturally with disease progression. The 12-month change was 2.4±5.2 (cycling) and 2.2±5.7 (control). ADAS-Cog did not differ between groups at 6 (p = 0.386) and 12 months (p = 0.856). There were no differences in the 12-month rate of change in ADAS-Cog (0.192 versus 0.197, p = 0.967), memory (–0.012 versus –0.019, p = 0.373), executive function (–0.020 versus –0.012, p = 0.383), attention (–0.035 versus –0.033, p = 0.908), or language (–0.028 versus –0.026, p = 0.756). Conclusion: Exercise may reduce decline in global cognition in older adults with mild-to-moderate AD dementia. Aerobic exercise did not show superior cognitive effects to stretching in our pilot trial, possibly due to the lack of power.

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Disruption of the astrocyte–neuron interaction is responsible for the impairments in learning and memory in 5XFAD mice: an Alzheimer’s disease animal model

Molecular Brain ◽

10.1186/s13041-021-00823-5 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Moonseok Choi ◽

Sang-Min Lee ◽

Dongsoo Kim ◽

Heh-In Im ◽

Hye-Sun Kim ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Animal Model ◽

Memory Formation ◽

Long Term Memory ◽

Term Memory ◽

Stat3 Phosphorylation ◽

Neuron Interactions ◽

5Xfad Mice

AbstractThe morphological dynamics of astrocytes are altered in the hippocampus during memory induction. Astrocyte–neuron interactions on synapses are called tripartite synapses. These control the synaptic function in the central nervous system. Astrocytes are activated in a reactive state by STAT3 phosphorylation in 5XFAD mice, an Alzheimer’s disease (AD) animal model. However, changes in astrocyte–neuron interactions in reactive or resting-state astrocytes during memory induction remain to be defined. Here, we investigated the time-dependent changes in astrocyte morphology and the number of astrocyte–neuron interactions in the hippocampus over the course of long-term memory formation in 5XFAD mice. Hippocampal-dependent long-term memory was induced using a contextual fear conditioning test in 5XFAD mice. The number of astrocytic processes increased in both wild-type and 5XFAD mice during memory formation. To assess astrocyte–neuron interactions in the hippocampal dentate gyrus, we counted the colocalization of glial fibrillary acidic protein and postsynaptic density protein 95 via immunofluorescence. Both groups revealed an increase in astrocyte–neuron interactions after memory induction. At 24 h after memory formation, the number of tripartite synapses returned to baseline levels in both groups. However, the total number of astrocyte–neuron interactions was significantly decreased in 5XFAD mice. Administration of Stattic, a STAT3 phosphorylation inhibitor, rescued the number of astrocyte–neuron interactions in 5XFAD mice. In conclusion, we suggest that a decreased number of astrocyte–neuron interactions may underlie memory impairment in the early stages of AD.

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Alterations in the Gut-Microbial-Inflammasome-Brain Axis in a Mouse Model of Alzheimer’s Disease

Cells ◽

10.3390/cells10040779 ◽

2021 ◽

Vol 10 (4) ◽

pp. 779

Author(s):

Pradeep K. Shukla ◽

David F. Delotterie ◽

Jianfeng Xiao ◽

Joseph F. Pierre ◽

RadhaKrishna Rao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Gut Microbiota ◽

Transgenic Mice ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Gut Barrier Function ◽

Elevated Expression ◽

5Xfad Mice

Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive decline, is a major cause of death and disability among the older population. Despite decades of scientific research, the underlying etiological triggers are unknown. Recent studies suggested that gut microbiota can influence AD progression; however, potential mechanisms linking the gut microbiota with AD pathogenesis remain obscure. In the present study, we provided a potential mechanistic link between dysbiotic gut microbiota and neuroinflammation associated with AD progression. Using a mouse model of AD, we discovered that unfavorable gut microbiota are correlated with abnormally elevated expression of gut NLRP3 and lead to peripheral inflammasome activation, which in turn exacerbates AD-associated neuroinflammation. To this end, we observe significantly altered gut microbiota compositions in young and old 5xFAD mice compared to age-matched non-transgenic mice. Moreover, 5xFAD mice demonstrated compromised gut barrier function as evident from the loss of tight junction and adherens junction proteins compared to non-transgenic mice. Concurrently, we observed increased expression of NLRP3 inflammasome and IL-1β production in the 5xFAD gut. Consistent with our hypothesis, increased gut–microbial–inflammasome activation is positively correlated with enhanced astrogliosis and microglial activation, along with higher expression of NLRP3 inflammasome and IL-1β production in the brains of 5xFAD mice. These data indicate that the elevated expression of gut–microbial–inflammasome components may be an important trigger for subsequent downstream activation of inflammatory and potentially cytotoxic mediators, and gastrointestinal NLRP3 may promote NLRP3 inflammasome-mediated neuroinflammation. Thus, modulation of the gut microbiota may be a potential strategy for the treatment of AD-related neurological disorders in genetically susceptible hosts.

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Impact of Gut Microbiome Manipulation in 5xFAD Mice on Alzheimer’s Disease-Like Pathology

Microorganisms ◽

10.3390/microorganisms9040815 ◽

2021 ◽

Vol 9 (4) ◽

pp. 815

Author(s):

Malena dos Santos Guilherme ◽

Vu Thu Thuy Nguyen ◽

Christoph Reinhardt ◽

Kristina Endres

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gut Microbiome ◽

Microbial Composition ◽

Aβ Peptides ◽

Plaque Deposition ◽

Glycation End Products ◽

Plaque Load ◽

5Xfad Mice ◽

Building Capability

The gut brain axis seems to modulate various psychiatric and neurological disorders such as Alzheimer’s disease (AD). Growing evidence has led to the assumption that the gut microbiome might contribute to or even present the nucleus of origin for these diseases. In this regard, modifiers of the microbial composition might provide attractive new therapeutics. Aim of our study was to elucidate the effect of a rigorously changed gut microbiome on pathological hallmarks of AD. 5xFAD model mice were treated by antibiotics or probiotics (L. acidophilus and L. rhamnosus) for 14 weeks. Pathogenesis was measured by nest building capability and plaque deposition. The gut microbiome was affected as expected: antibiotics significantly reduced viable commensals, while probiotics transiently increased Lactobacillaceae. Nesting score, however, was only improved in antibiotics-treated mice. These animals additionally displayed reduced plaque load in the hippocampus. While various physiological parameters were not affected, blood sugar was reduced and serum glucagon level significantly elevated in the antibiotics-treated animals together with a reduction in the receptor for advanced glycation end products RAGE—the inward transporter of Aβ peptides of the brain. Assumedly, the beneficial effect of the antibiotics was based on their anti-diabetic potential.

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Effects of optogenetic stimulation of basal forebrain parvalbumin neurons on Alzheimer’s disease pathology

Scientific Reports ◽

10.1038/s41598-020-72421-9 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Caroline A. Wilson ◽

Sarah Fouda ◽

Shuzo Sakata

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Basal Forebrain ◽

Gamma Oscillations ◽

Cortical Region ◽

Sensory Stimuli ◽

Beneficial Effects ◽

Amyloid Load ◽

5Xfad Mice ◽

Frontal Cortical Region

Abstract Neuronal activity can modify Alzheimer’s disease pathology. Overexcitation of neurons can facilitate disease progression whereas the induction of cortical gamma oscillations can reduce amyloid load and improve cognitive functions in mouse models. Although previous studies have induced cortical gamma oscillations by either optogenetic activation of cortical parvalbumin-positive (PV+) neurons or sensory stimuli, it is still unclear whether other approaches to induce gamma oscillations can also be beneficial. Here we show that optogenetic activation of PV+ neurons in the basal forebrain (BF) increases amyloid burden, rather than reducing it. We applied 40 Hz optical stimulation in the BF by expressing channelrhodopsin-2 (ChR2) in PV+ neurons of 5xFAD mice. After 1-h induction of cortical gamma oscillations over three days, we observed the increase in the concentration of amyloid-β42 in the frontal cortical region, but not amyloid-β40. Amyloid plaques were accumulated more in the medial prefrontal cortex and the septal nuclei, both of which are targets of BF PV+ neurons. These results suggest that beneficial effects of cortical gamma oscillations on Alzheimer’s disease pathology can depend on the induction mechanisms of cortical gamma oscillations.

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Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice

Antioxidants ◽

10.3390/antiox8120630 ◽

2019 ◽

Vol 8 (12) ◽

pp. 630 ◽

Cited By ~ 6

Author(s):

Donald G Matthews ◽

Maya Caruso ◽

Charles F Murchison ◽

Jennifer Y Zhu ◽

Kirsten M Wright ◽

...

Keyword(s):

Oxidative Stress ◽

Amyloid Β ◽

Water Extract ◽

Centella Asiatica ◽

Antioxidant Response ◽

Plaque Burden ◽

Heme Oxygenase 1 ◽

Synaptic Density ◽

Cognitive Benefits ◽

5Xfad Mice

Centella asiatica (CA) herb is a traditional medicine, long reputed to provide cognitive benefits. We have reported that CA water extract (CAW) treatment improves cognitive function of aged Alzheimer’s disease (AD) model Tg2576 and wild-type (WT) mice, and induces an NRF2-regulated antioxidant response in aged WT mice. Here, CAW was administered to AD model 5XFAD female and male mice and WT littermates (age: 7.6 +/ − 0.6 months), and object recall and contextual fear memory were tested after three weeks treatment. CAW’s impact on amyloid-β plaque burden, and markers of neuronal oxidative stress and synaptic density, was assessed after five weeks treatment. CAW antioxidant activity was evaluated via nuclear transcription factor (erythroid-derived 2)-like 2 (NRF2) and NRF2-regulated antioxidant response element gene expression. Memory improvement in both genders and genotypes was associated with dose-dependent CAW treatment without affecting plaque burden, and marginally increased synaptic density markers in the hippocampus and prefrontal cortex. CAW treatment increased Nrf2 in hippocampus and other NRF2 targets (heme oxygenase-1, NAD(P)H quinone dehydrogenase 1, glutamate-cysteine ligase catalytic subunit). Reduced plaque-associated SOD1, an indicator of oxidative stress, was observed in the hippocampi and cortices of CAW-treated 5XFAD mice. We postulate that CAW treatment leads to reduced oxidative stress, contributing to improved neuronal health and cognition.

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