Probiotics Fermentation Technology, a Novel Kefir Product, Ameliorates Cognitive Impairment in Streptozotocin-Induced Sporadic Alzheimer’s Disease in Mice

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by cognitive impairment. Gut microbiota dysfunction (dysbiosis) is implicated in the pathology of AD and is associated with several detrimental consequences, including neurotransmitter depletion, oxidative stress, inflammation, apoptosis, and insulin resistance, which all contribute to the onset of AD. The objective of this study was to assess the effectiveness of Probiotics Fermentation Technology (PFT), a kefir product, in alleviating AD symptoms via regulation of the gut microbiota using a streptozotocin- (STZ-) induced AD mouse model and to compare its activity with simvastatin, which has been proven to effectively treat AD. Mice received one intracerebroventricular injection of STZ (3 mg/kg). PFT (100, 300, 600 mg/kg) and simvastatin (20 mg/kg) were administered orally for 3 weeks. PFT supplementation mitigated STZ-induced neuronal degeneration in the cortex and hippocampus, restored hippocampal acetylcholine levels, and improved cognition in a dose-dependent manner. These effects were accompanied by reductions in oxidative damage, proinflammatory cytokine expression, apoptosis, and tau hyperphosphorylation. Moreover, PFT hindered amyloid plaque accumulation via the enhancement of insulin-degrading enzyme. These beneficial effects were comparable to those produced by simvastatin. The results suggest that PFT can alleviate AD symptoms by regulating the gut microbiota and by inhibiting AD-related pathological events.

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Gut Microbiota Alterations and Cognitive Impairment Are Sexually Dissociated in a Transgenic Mice Model of Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-201367 ◽

2021 ◽

pp. 1-20

Author(s):

Daniel Cuervo-Zanatta ◽

Jaime Garcia-Mena ◽

Claudia Perez-Cruz

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Gut Microbiota ◽

Cognitive Skills ◽

Amyloid Β ◽

Short Chain Fatty Acids ◽

Mice Model ◽

Model Of Alzheimer’S Disease ◽

Cognitive Deficiencies

Background: Normal aging is accompanied by cognitive deficiencies, affecting women and men equally. Aging is the main risk factor for Alzheimer’s disease (AD), with women having a higher risk. The higher prevalence of AD in women is associated with the abrupt hormonal decline seen after menopause. However, other factors may be involved in this sex-related cognitive decline. Alterations in gut microbiota (GM) and its bioproducts have been reported in AD subjects and transgenic (Tg) mice, having a direct impact on brain amyloid-β pathology in male (M), but not in female (F) mice. Objective: The aim of this work was to determine GM composition and cognitive dysfunction in M and F wildtype (WT) and Tg mice, in a sex/genotype segregation design. Methods: Anxiety, short term working-memory, spatial learning, and long-term spatial memory were evaluated in 6-month-old WT and Tg male mice. Fecal short chain fatty acids were determined by chromatography, and DNA sequencing and bioinformatic analyses were used to determine GM differences. Results: We observed sex-dependent differences in cognitive skills in WT mice, favoring F mice. However, the cognitive advantage of females was lost in Tg mice. GM composition showed few sex-related differences in WT mice. Contrary, Tg-M mice presented a more severe dysbiosis than Tg-F mice. A decreased abundance of Ruminococcaceae was associated with cognitive deficits in Tg-F mice, while butyrate levels were positively associated with better working- and object recognition-memory in WT-F mice. Conclusion: This report describes a sex-dependent association between GM alterations and cognitive impairment in a mice model of AD.

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Mild cognitive impairment has similar alterations as Alzheimer's disease in gut microbiota

Alzheimer s & Dementia ◽

10.1016/j.jalz.2019.07.002 ◽

2019 ◽

Vol 15 (10) ◽

pp. 1357-1366 ◽

Cited By ~ 24

Author(s):

Binyin Li ◽

Yixi He ◽

Jianfang Ma ◽

Pei Huang ◽

Juanjuan Du ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Gut Microbiota

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Green Tea Seed Isolated Theasaponin E1 Ameliorates AD Promoting Neurotoxic Pathogenesis by Attenuating Aβ Peptide Levels in SweAPP N2a Cells

Molecules ◽

10.3390/molecules25102334 ◽

2020 ◽

Vol 25 (10) ◽

pp. 2334 ◽

Cited By ~ 1

Author(s):

Muhammad Imran Khan ◽

Jin Hyuk Shin ◽

Min Yong Kim ◽

Tai Sun Shin ◽

Jong Deog Kim

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Green Tea ◽

Neuroblastoma Cells ◽

Dependent Manner ◽

Insulin Degrading Enzyme ◽

App Processing ◽

N2a Cells ◽

Gene And Protein Expression ◽

Dose Dependent

Alzheimer’s disease (AD) is the most frequent type of dementia affecting memory, thinking and behaviour. The major hallmark of the disease is pathological neurodegeneration due to abnormal aggregation of Amyloid beta (Aβ) peptides generated by β- and γ-secretases via amyloidogenic pathway. Purpose of the current study was to evaluate the effects of theasaponin E1 on the inhibition of Aβ producing β-, γ-secretases (BACE1, PS1 and NCT) and acetylcholinesterase and activation of the non-amyloidogenic APP processing α-secretase (ADAM10). Additionally, theasaponin E1 effects on Aβ degrading and clearing proteins neprilysin and insulin degrading enzyme (IDE). The effect of theasaponin E1 on these crucial enzymes was investigated by RT-PCR, ELISA, western blotting and fluorometric assays using mouse neuroblastoma cells (SweAPP N2a). theasaponin E1 was extracted and purified from green tea seed extract via HPLC, and N2a cells were treated with different concentrations for 24 h. Gene and protein expression in the cells were measured to determine the effects of activation and/or inhibition of theasaponin E1 on β- and γ-secretases, neprilysin and IDE. Results demonstrated that theasaponin E1 significantly reduced Aβ concentration by activation of the α-secretase and neprilysin. The activities of β- and γ-secretase were reduced in a dose-dependent manner due to downregulation of BACE1, presenilin, and nicastrin. Similarly, theasaponin E1 significantly reduced the activity of acetylcholinesterase. Overall, from the results it is concluded that green tea seed extracted saponin E1 possess therapeutic significance as a neuroprotective natural product recommended for the treatment of Alzheimer’s disease.

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Strategic Modification of Gut Microbiota through Oral Bacteriotherapy Influences Hypoxia Inducible Factor-1α: Therapeutic Implication in Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms23010357 ◽

2021 ◽

Vol 23 (1) ◽

pp. 357

Author(s):

Laura Bonfili ◽

Chunmei Gong ◽

Francesca Lombardi ◽

Maria Grazia Cifone ◽

Anna Maria Eleuteri

Keyword(s):

Nitric Oxide ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gut Microbiota ◽

Hypoxia Inducible Factor ◽

Blood Oxygenation ◽

Tau Proteins ◽

Hypoxia Inducible Factor 1Α ◽

Beneficial Effects ◽

Cerebral Blood Oxygenation

Dysbiosis contributes to Alzheimer’s disease (AD) pathogenesis, and oral bacteriotherapy represents a promising preventative and therapeutic opportunity to remodel gut microbiota and to delay AD onset and progression by reducing neuroinflammation and amyloid and tau proteins aggregation. Specifically, SLAB51 multi-strain probiotic formulation positively influences multiple neuro-chemical pathways, but exact links between probiotics oral consumption and cerebral beneficial effects remain a gap of knowledge. Considering that cerebral blood oxygenation is particularly reduced in AD and that the decreased neurovascular function contributes to AD damages, hypoxia conditioning represents an encouraging strategy to cure diseases of the central nervous system. In this work, 8-week-old 3xTg-AD and wild-type mice were chronically supplemented with SLAB51 to evaluate effects on hypoxia-inducible factor-1α (HIF-1α), a key molecule regulating host-microbial crosstalk and a potential target in neurodegenerative pathologies. We report evidence that chronic supplementation with SLAB51 enhanced cerebral expression of HIF-1α and decreased levels of prolyl hydroxylase 2 (PHD2), an oxygen dependent regulator of HIF-1α degradation; moreover, it successfully counteracted the increase of inducible nitric oxide synthase (iNOS) brain expression and nitric oxide plasma levels in AD mice. Altogether, the results demonstrate an additional mechanism through which SLAB51 exerts neuroprotective and anti-inflammatory effects in this model of AD.

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Gut microbiota regulate Alzheimer’s disease pathologies and cognitive disorders via PUFA-associated neuroinflammation

Gut ◽

10.1136/gutjnl-2021-326269 ◽

2022 ◽

pp. gutjnl-2021-326269

Author(s):

Chun Chen ◽

Jianming Liao ◽

Yiyuan Xia ◽

Xia Liu ◽

Rheinallt Jones ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gut Microbiota ◽

Gut Microbiome ◽

Amyloid Β ◽

Microglia Activation ◽

Oxidative Enzymes ◽

Dependent Manner ◽

Germ Free ◽

Healthy Donors

ObjectiveThis study is to investigate the role of gut dysbiosis in triggering inflammation in the brain and its contribution to Alzheimer’s disease (AD) pathogenesis.DesignWe analysed the gut microbiota composition of 3×Tg mice in an age-dependent manner. We generated germ-free 3×Tg mice and recolonisation of germ-free 3×Tg mice with fecal samples from both patients with AD and age-matched healthy donors.ResultsMicrobial 16S rRNA sequencing revealed Bacteroides enrichment. We found a prominent reduction of cerebral amyloid-β plaques and neurofibrillary tangles pathology in germ-free 3×Tg mice as compared with specific-pathogen-free mice. And hippocampal RNAseq showed that inflammatory pathway and insulin/IGF-1 signalling in 3×Tg mice brain are aberrantly altered in the absence of gut microbiota. Poly-unsaturated fatty acid metabolites identified by metabolomic analysis, and their oxidative enzymes were selectively elevated, corresponding with microglia activation and inflammation. AD patients’ gut microbiome exacerbated AD pathologies in 3×Tg mice, associated with C/EBPβ/asparagine endopeptidase pathway activation and cognitive dysfunctions compared with healthy donors’ microbiota transplants.ConclusionsThese findings support that a complex gut microbiome is required for behavioural defects, microglia activation and AD pathologies, the gut microbiome contributes to pathologies in an AD mouse model and that dysbiosis of the human microbiome might be a risk factor for AD.

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Clinical and neuropathological correlates of depression in Alzheimer's disease

Psychological Medicine ◽

10.1017/s0033291700038459 ◽

1992 ◽

Vol 22 (4) ◽

pp. 877-884 ◽

Cited By ~ 131

Author(s):

Hans Förstl ◽

Alistair Burns ◽

Philip Luthert ◽

Nigel Cairns ◽

Peter Lantos ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Age Of Onset ◽

Neuronal Degeneration ◽

Cholinergic Neurons ◽

Organic Substrate ◽

Basal Nucleus ◽

Alzheimer Pathology ◽

Basal Nucleus Of Meynert

SynopsisDepressive symptoms have been reported in patients with mild to moderate Alzheimer's disease (AD). Recent evidence suggests that a noradrenergic deficit originating from neuronal degeneration in brainstem nuclei may represent an organic correlate of these disturbances. We examined the neuropathological changes in the locus coeruleus (LC), substantia nigra (SN), basal nucleus of Meynert and cortex of 52 patients (12 male, 40 female, mean age 83·2 ± 6·4 years) with pathologically verified AD. Fourteen patients (1 male, 13 female) showed signs of depression. The majority of these patients suffered from severe physical disability or sensory impairment and developed persistent delusions, but had less cognitive impairment. Neuronal counts in the LC were significantly lower than in the 38 patients without depression (36·9 ± 14 ·0; 51·4 ± 28·0 neuromelaninpigmented cells per section per nucleus;F= 3·4, df = 1, 50,P= 0·04). Neuron counts were higher in the basal nucleus of Meynert in depressed AD patients and there were no differences of the neuron numbers in the SN. Depression (main effect;F= 4·5,P= 0·04) contributed significantly to the variance of neuronal counts in the LC, even when covarying for gender, age of onset, cognitive impairment and cortical Alzheimer pathology. The observed disproportionate loss of noradrenergic and cholinergic neurons in the LC and basal nucleus of Meynert may represent an important organic substrate of depression in AD.

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Short-term resistance exercise inhibits neuroinflammation and attenuates neuropathological changes in 3xTg Alzheimer’s disease mice

Journal of Neuroinflammation ◽

10.1186/s12974-019-1653-7 ◽

2020 ◽

Vol 17 (1) ◽

Cited By ~ 8

Author(s):

Yan Liu ◽

John Man Tak Chu ◽

Tim Yan ◽

Yan Zhang ◽

Ying Chen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Cognitive Function ◽

Resistance Training ◽

Resistance Exercise ◽

The Elderly ◽

Short Term ◽

Neuroprotective Effects ◽

Beneficial Effects

Abstract Background Both human and animal studies have shown beneficial effects of physical exercise on brain health but most tend to be based on aerobic rather than resistance type regimes. Resistance exercise has the advantage of improving both muscular and cardiovascular function, both of which can benefit the frail and the elderly. However, the neuroprotective effects of resistance training in cognitive impairment are not well characterized. Methods We evaluated whether short-term resistant training could improve cognitive function and pathological changes in mice with pre-existing cognitive impairment. Nine-month-old 3xTg mouse underwent a resistance training protocol of climbing up a 1-m ladder with a progressively heavier weight loading. Results Compared with sedentary counterparts, resistance training improved cognitive performance and reduced neuropathological and neuroinflammatory changes in the frontal cortex and hippocampus of mice. In line with these results, inhibition of pro-inflammatory intracellular pathways was also demonstrated. Conclusions Short-term resistance training improved cognitive function in 3xTg mice, and conferred beneficial effects on neuroinflammation, amyloid and tau pathology, as well as synaptic plasticity. Resistance training may represent an alternative exercise strategy for delaying disease progression in Alzheimer’s disease.

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Raloxifene as Treatment for Various Types of Brain Injuries and Neurodegenerative Diseases: A Good Start

International Journal of Molecular Sciences ◽

10.3390/ijms21207586 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7586

Author(s):

Leo Veenman

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Culture ◽

Clinical Trials ◽

Cell Death ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Impairments ◽

Beneficial Effects

Recent studies have shown that the selective estrogen receptor modulator (SERM) raloxifene had pronounced protective effects against progressing brain damage after traumatic brain injury (TBI) in mice. These studies, indicating beneficial effects of raloxifene for brain health, prompted the study of the history and present state of knowledge of this topic. It appears that, apart from raloxifene, to date, four nonrelated compounds have shown comparable beneficial effects—fucoidan, pifithrin, SMM-189 (5-dihydroxy-phenyl]-phenyl-methanone), and translocator protein (TSPO) ligands. Raloxifene, however, is ahead of the field, as for more than two decades it has been used in medical practice for various chronic ailments in humans. Thus, apart from different types of animal and cell culture studies, it has also been assessed in various human clinical trials, including assaying its effects on mild cognitive impairments. Regarding cell types, raloxifene protects neurons from cell death, prevents glial activation, ameliorates myelin damage, and maintains health of endothelial cells. At whole central nervous system (CNS) levels, raloxifene ameliorated mild cognitive impairments, as seen in clinical trials, and showed beneficial effects in animal models of Parkinson’s disease. Moreover, with stroke and TBI in animal models, raloxifene showed curative effects. Furthermore, raloxifene showed healing effects regarding multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) in cell culture. The adverse biological signals typical of these conditions relate to neuronal activity, neurotransmitters and their receptors, plasticity, inflammation, oxidative stress, nitric oxide, calcium homeostasis, cell death, behavioral impairments, etc. Raloxifene favorably modulates these signals toward cell health—on the one hand, by modulating gene expression of the relevant proteins, for example by way of its binding to the cell nuclear estrogen receptors ERα and ERβ (genomic effects) and, on the other hand (nongenomic effects) by modulation of mitochondrial activity, reduction of oxidative stress and programmed cell death, maintaining metabolic balance, degradation of Abeta, and modulation of intracellular cholesterol levels. More specifically regarding Alzheimer’s disease, raloxifene may not cure diagnosed Alzheimer’s disease. However, the onset of Alzheimer’s disease may be delayed or arrested by raloxifene’s capability to attenuate mild cognitive impairment. Mild cognitive impairment is a condition that may precede diagnosis of Alzheimer’s disease. In this review, relatively new insights are addressed regarding the notion that Alzheimer’s disease can be caused by bacterial (as well as viral) infections, together with the most recent findings that raloxifene can counteract infections of at least some bacterial and viral strains. Thus, here, an overview of potential treatments of neurodegenerative disease by raloxifene is presented, and attention is paid to subcellular molecular biological pathways that may be involved.

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Potential of Caffeine in Alzheimer’s Disease—A Review of Experimental Studies

Nutrients ◽

10.3390/nu13020537 ◽

2021 ◽

Vol 13 (2) ◽

pp. 537

Author(s):

Piotr Londzin ◽

Milena Zamora ◽

Beata Kąkol ◽

Aleksandra Taborek ◽

Joanna Folwarczna

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Treatment Options ◽

Experimental Studies ◽

Memory Loss ◽

Epidemiological Data ◽

Caffeine Intake ◽

Protective Mechanisms ◽

Beneficial Effects

Alzheimer’s disease (AD) is the most common type of dementia leading to progressive memory loss and cognitive impairment. Considering that pharmacological treatment options for AD are few and not satisfactory, increasing attention is being paid to dietary components that may affect the development of the disease. Such a dietary component may be caffeine contained in coffee, tea or energy drinks. Although epidemiological data suggest that caffeine intake may counteract the development of cognitive impairment, results of those studies are not conclusive. The aim of the present study is to review the existing experimental studies on the efficacy of caffeine against AD and AD-related cognitive impairment, focusing on the proposed protective mechanisms of action. In conclusion, the reports of studies on experimental AD models generally supported the notion that caffeine may exert some beneficial effects in AD. However, further studies are necessary to elucidate the role of caffeine in the effects of its sources on cognition and possibly AD risk.

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Pharmacological inhibition of soluble epoxide hydrolase as a new therapy for Alzheimer’s Disease

10.1101/605055 ◽

2019 ◽

Cited By ~ 2

Author(s):

Christian Griñán-Ferré ◽

Sandra Codony ◽

Eugènia Pujol ◽

Jun Yang ◽

Rosana Leiva ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Therapeutic Effects ◽

Beneficial Effects ◽

Age Related ◽

Novel Target ◽

Age Related Cognitive Decline

AbstractThe inhibition of the enzyme soluble epoxide hydrolase (sEH) has demonstrated clinical therapeutic effects in several peripheral inflammatory-related diseases, with two compounds that have entered clinical trials. However, the role of this enzyme in the neuroinflammation process has been largely neglected. Herein, we disclose the pharmacological validation of sEH as a novel target for the treatment of Alzheimer’s Disease (AD). Of interest, we have found that sEH is upregulated in brains from AD patients. We have evaluated the cognitive impairment and the pathological hallmarks in two models of age-related cognitive decline and AD using three structurally different and potent sEH inhibitors as chemical probes. Our findings supported our expectations on the beneficial effects of central sEH inhibition, regarding of reducing cognitive impairment, tau hyperphosphorylation pathology and the number of amyloid plaques. Interestingly, our results suggest that reduction of inflammation in the brain is a relevant therapeutic strategy for all stages of AD.

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