Alzheimer's Disease Mouse Model Research Articles

Thorase deficiency causes both Aβ accumulation and tau hyperphosphorylation in mouse brain

AbstractINTRODUCTIONThe pathogenesis of two major pathogenic characters—amyloid beta (Aβ) accumulation and hyperphosphorylated tau protein—in the brains of patients with Alzheimer's disease (AD) remains unclear.METHODSWestern blot and immunofluorescence staining were performed to detect the proteins in the brains of Thorase conditional knockout/transgenic mice and their littermates. A co‐immunoprecipitation assay was applied to examine the Thorase‐interacting proteins.RESULTSGenetic deletion of Thorase resulted in tau hyperphosphorylation and promoted Aβ accumulation in the mouse brain. Conversely, Thorase overexpression alleviated the pathogenesis of AD. Thorase regulated the phosphorylation of tau by targeting specific kinases and theprotein phosphatase 2B (PP2B). Thorase deficiency also impaired microglial phagocytosis and induced neuroinflammation by the activation of the NOD‐like receptor thermal protein domain associated protein 3 (NLRP3) inflammasomes in microglia.DISCUSSIONThorase may be a potential druggable target for developing therapeutic approaches to treat AD and other neurodegenerative diseases.Highlights Thorase deletion leads to elevated amyloid beta (Aβ) deposition and hyperphosphorylated tau accumulation in the brain. Thorase regulates the phosphorylation of tau protein via PP2B. Thorase deficiency impairs microglial phagocytosis and promotesNLRP3‐mediated neuroinflammation. Overexpression of Thorase alleviates Aβ deposition and tau phosphorylation in the AD mouse model.

ACSL3 is a promising therapeutic target for alleviating anxiety and depression in Alzheimer’s disease

AbstractAlzheimer’s disease (AD), the leading cause of dementia, affects over 55 million people worldwide and is often accompanied by depression and anxiety. Both significantly impact patients’ quality of life and impose substantial societal and economic burdens on healthcare systems. Identifying the complex regulatory mechanisms that contribute to the psychological and emotional deficits in AD will provide promising therapeutic targets. Biosynthesis of omega-3 (ω3) and omega-6 fatty acids (ω6-FA) through long-chain acyl-CoA synthetases (ACSL) is crucial for cell function and survival. This is due to ω3/6-FA’s imperative role in modulating the plasma membrane, energy production, and inflammation. While ACSL dysfunction is known to cause heart, liver, and kidney diseases, the role of ACSL in pathological conditions in the central nervous system (e.g., depression and anxiety) remains largely unexplored. The impact of ACSLs on AD-related depression and anxiety was investigated in a mouse model of Alzheimer’s disease (3xTg-AD). ACSL3 levels were significantly reduced in the hippocampus of aged 3xTg-AD mice (via capillary-based immunoassay). This reduction in ACAL3 was closely associated with increased depression and anxiety-like behavior (via forced swim, tail suspension, elevated plus maze, and sucrose preference test). Upregulation of ACSL3 via adenovirus in aged 3xTg-AD mice led to increased protein levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor C (VEGF-C) (via brain histology, capillary-based immunoassay), resulting in alleviation of depression and anxiety symptoms. The present study highlights a novel neuroprotective role of ACSL3 in the brain. Targeting ACSL3 will offer an innovative approach for treating AD-related depression and anxiety.

Contextual Fear Conditioning Uncovers Spine and Learning Deficits in the Retrosplenial Cortex in a Familial Alzheimer’s Disease Mouse Model

While excitatory synapse loss is documented in the brains of Alzheimer’s Disease (AD) patients, its role in episodic learning decline, one of the first evident AD symptoms, is unclear. The retrosplenial cortex (RSC), a cortical structure required for episodic learning, provides an ideal entry point to study the role of synapse loss in cognitive decline in AD since it is a site of high amyloid load and dysfunctional early in AD progression. Further, excitatory synapse assembly, both turnover and clustered synapse formation, is highly correlated with episodic learning performance in the RSC. We hypothesize alterations in synapse assembly in the RSC of AD patients contribute to early cognitive decline in the disease. To address this hypothesis, we examined both excitatory synapse density in the RSC and contextual learning in a familial AD (fAD) mouse model, an early onset amyloid model of AD. Importantly, we find age-dependent excitatory synapse loss in the RSC of fAD mice, as measured by imaging and quantification of GFP-labeled dendritic spines. Further, prior to frank spine loss in 5-month-old fAD mice we found episodic learning deficits, as measured by contextual fear conditioning (CFC). Using this early time point, we examined spine dynamics in vivo with MP imaging in the RSC of fAD mice or controls while engaged in CFC learning. Interestingly, we find deficits both in spine turnover and clustered spine formation and a loss of correlations of these spine metrics with CFC performance, suggesting aberrant spine dynamics may be causal in episodic learning deficits in this AD model, consistent with our hypothesis. Future studies will pharmacologically target these aberrant spine dynamics in fAD mice in an effort to strengthen the causal link between alterations in synapse assembly and cognitive decline in AD as well as provide potential therapeutic approaches to reverse early stages of the disease.

APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia

AbstractThe major genetic risk factor for Alzheimer’s disease (AD), APOE4, accelerates beta-amyloid (Aβ) plaque formation, but whether this is caused by APOE expressed in microglia or astrocytes is debated. We express here the human APOE isoforms in astrocytes in an Apoe-deficient AD mouse model. This is not only sufficient to restore the amyloid plaque pathology but also induces the characteristic transcriptional pathological responses in Apoe-deficient microglia surrounding the plaques. We find that both APOE4 and the protective APOE2 from astrocytes increase fibrillar plaque deposition, but differentially affect soluble Aβ aggregates. Microglia and astrocytes show specific alterations in function of APOE genotype expressed in astrocytes. Our experiments indicate a central role of the astrocytes in APOE mediated amyloid plaque pathology and in the induction of associated microglia responses.

Alterations in Zinc, Copper, and Iron Levels in the Retina and Brain of Alzheimer's Disease Patients and the APP/PS1 Mouse Model

ABSTRACT Transition metals like copper, iron, and zinc are vital for normal central nervous system function and are also linked to neurodegeneration, particularly in the onset and progression of Alzheimer's disease (AD). Their alterations in AD, identified prior to amyloid plaque aggregation, offer a unique target for staging pre-amyloid AD. However, analysing their levels in the brain is extremely challenging, necessitating the development of alternative approaches. Here, we utilised laser ablation-inductively coupled plasma-mass spectrometry and solution nebulisation-inductively coupled plasma-mass spectrometry to quantitatively measure Cu, Fe, and Zn concentrations in the retina and hippocampus samples obtained from human donors (i.e., AD and healthy controls), and in the APP/PS1 mouse model of AD, and Wild Type controls, aged 9 and 18 months. Our findings revealed significantly elevated Cu, Fe, and Zn levels in the retina (*p < 0.05, **p < 0.01, ***p < 0.001) and hippocampus (*p < 0.05, *p < 0.05, *p < 0.05) of human AD samples compared to healthy controls. Conversely, APP/PS1 mouse models exhibited notably lower metal levels in the same regions compared to WT mice, Cu, Fe, and Zn levels in the retina (**p < 0.01, *p < 0.05, *p < 0.05) and hippocampus (**p < 0.01, **p < 0.01, *p < 0.05). The contrasting metal profiles in human and mouse samples, yet similar patterns within each species' retina and brain, suggest the retina mirrors cerebral metal dyshomeostasis in AD. Our findings lay the groundwork for staging pre-AD pathophysiology through assessment of transition metal levels in the retina.

Tau, synapse loss and gliosis progress in an Alzheimer's mouse model after amyloid-β immunotherapy.

While preclinical studies assessing drugs for Alzheimer's disease (AD) are conducted in animal models that usually display only one neuropathological feature of AD, patients present with a complex combination of comorbidities and neuropathologies. Importantly, it is well-established that amyloid (Aβ) plaque and tau tangle accumulation interact in a phase-dependent manner, making it difficult to predict how targeting one might influence the other, as well as downstream degeneration. We developed a transgenic mouse model, APP/PS1xTau22, with progressive cortical Aβ deposition and hippocampal tau neurofibrillary inclusions to investigate how both neuropathologies act jointly to bring about neural degeneration, synapse loss, and glial phenotypes. We then assessed whether applying murine chimeric Aducanumab, an anti-amyloid immunotherapy, could impact the synergistic relationship between amyloid and tau. Drug treatment resulted in a ∼70% reduction in Aβ deposition in hippocampal and cortical areas and produced a robust peri-plaque microglial and astrocytic response. Removing amyloid from the brain did not reverse or slow tau pathology or alter synapse loss. Our findings suggest that, once the interaction between amyloid and tau is set in motion, reducing plaque burden by Aβ immunotherapy may stimulate glial responses, but is insufficient to curb degenerative phenotypes in this model.

Navigating Alzheimer’s Disease Mouse Models: Age-Related Pathology and Cognitive Deficits

Since the mid-1990s, scientists have been generating mouse models of Alzheimer’s disease to elucidate key mechanisms underlying the onset and progression of the disease and aid in developing potential therapeutic approaches. The first successful mouse model of Alzheimer’s disease was reported in 1995 with the generation of the PDAPP mice, which were obtained by the overexpression of gene coding for the amyloid precursor protein (APP). Since then, scientists have used different approaches to develop other APP overexpression mice, mice overexpressing tau, or a combination of them. More recently, Saito and colleagues generated a mouse model by knocking in mutations associated with familial Alzheimer’s disease into the APP gene. In this review, we will describe the most used animal models and provide a practical guide for the disease’s age of onset and progression. We believe that this guide will be valuable for the planning and experimental design of studies utilizing these mouse models.

Targeting Endogenous Tau in Seeded Tauopathy Models Inhibits Tau Spread.

The transmission of tau pathology has been proposed as one of the major mechanisms for the spatiotemporal spreading of tau pathology in neurodegenerative diseases. Over the last decade, studies have demonstrated that targeting total or pathological tau using tau antibodies can mitigate the development of tau pathology in tauopathy or Alzheimer's disease (AD) mouse models, and multiple tau immunotherapy agents have progressed to clinical trials. Tau antibodies are believed to inhibit the internalization of pathologic seeds and/or block seed elongation after seed internalization. To further address the mechanism of tau antibody inhibition of pathological spread, we conducted immunotherapy studies in mouse primary neurons and wild-type mice (females) seeded with AD patient-derived tau to induce the formation and spreading of tau pathology. Notably, we evaluated the effect of a mouse tau-specific antibody (mTau8) which does not interact with AD-tau seeds in these models. Our results show that mTau8 crosses the blood-brain barrier at levels similar to other antibodies and effectively decreases AD-tau-seeded tau pathology in vitro and in vivo. Importantly, our data suggest that mTau8 binds to endogenous intraneuronal mouse tau, thereby inhibiting the elongation of internalized tau seeds. These findings provide valuable insights into the possible mechanism underlying antibody-based therapies for treating tauopathies.Significance Statement The transmission of tau pathology plays key role in the pathoclinical progression of tauopathy. Studies have shown that tau antibody treatment can mitigate tau pathology in transgenic and spreading models of tauopathy. To explore the mechanisms involved in this procedure, we conducted immunotherapy studies on human tau seeds induced tau spreading models using a mouse tau-specific antibody (mTau8), which does not interact with human-tau seeds. Our findings in the study enhance our understanding of antibody-based therapies for tauopathies.

Effects of JAL-TA9 on cognitive deficits in Alzheimer's disease model mouse

Many studies have been conducted to find an effective drug for Alzheimer's disease (AD) treatment. However, no effective drug applicable for clinical use has been developed. Recently, the FDA approved Lecanemab, an antibody drug that acts as an aggregation inhibitor against Amyloid-beta (Aβ), for AD treatment. However, there are still no fundamental drugs for AD. In this study, we present a strategy for AD treatment that removes Aβ by cleavage reaction using one of the Catalytides, JAL-TA9 (YKGSGFRMI). A single dose of JAL-TA9 administered into the CA1 region of the hippocampus and the intraventricular space improved the deficits in short-term memory of APP-knock-in mice. It also improved the memory of Aβ25-35-induced model mice, as evaluated by the Y-maze and objective recognition tests. These data strongly suggest that JAL-TA9 could be effective in treating AD. However, these administration methods are difficult to apply clinically due to their high invasiveness. Thus, we tested the improvement effects of dementia by administering JAL-TA9 nasally. It is very interesting and exciting that the dementia of Aβ25-35 induced AD model mice was improved by four applications once every three days. These results strongly suggest that JAL-TA9 is the best candidate for AD treatment because it is effective even in the late stage of AD.

Possibility of short synthetic peptides with activities of suppressing amyloid β aggregation and resolving its aggregated form as therapeutic drugs for Alzheimer's disease

Lecanemab is a new anti-amyloid antibody being developed as a treatment for Alzheimer's disease. It is expected to delay the progression of the disease by reducing the accumulation of amyloid beta (Aβ) in the brain. However, no drug has been developed that can completely eliminate Aβ and improve symptoms. A representative Catalytide, JAL-TA9 (YKGSGFRMI), cleaves Aβ42 and improves symptoms in an Alzheimer's disease mouse model, suggesting that JAL-TA9 is a promising candidate for treating Alzheimer's disease by effectively eliminating Aβ. The catalytic center of JAL-TA9 is GSGFR. To identify better Catalytides for Alzheimer's treatment, we analyzed the structure-activity relationship of 21 point-mutated GSGFR derivatives. In this process, we discovered two peptides, GSGFK and GSGNR, that not only inhibit Aβ25-35 aggregation but also dissolve aggregated Aβ25-35. Intracerebroventricular administration of GSGFK protected mice against Aβ25-35-induced short-term memory deficits and promoted microglial phagocytic activity. Like Lecanemab, GSGFK targets Aβ, but it has advantages such as safety, administration method, and cost. In this talk, we will discuss the potential of GSGFK as a therapeutic candidate for Alzheimer's disease.

Berberine Modulates Microglial Polarization by Activating TYROBP in Alzheimer's Disease

BackgroundCharacterized by β-amyloid (Aβ) plaques, neurofibrillary tangles, and aberrant neuroinflammation in the brain, Alzheimer's disease (AD) is the most common neurodegenerative disease. Microglial polarization is a subtle mechanism which maintains immunological homeostasis and has emerged as a putative therapeutic to combat AD. Berberine (BBR) is a natural alkaloid compound with multiple pharmacological effects, and has shown considerable therapeutic potential against inflammatory disorders. However, BBR functions and underlying mechanisms in neuroinflammation remain unclear. PurposeTo examine BBR pharmacological effects and mechanisms in neuroinflammation with a view to treating AD. MethodsBBR effects on cognitive performance in 5 × FAD mice were assessed using open field, Y-maze, and Morris Water Maze (MWM) tests. Neuroinflammation-related markers and Aβ pathology were examined in brain sections from mice. Transcriptomic analyses of hippocampus tissues were also conducted. Microglial BV2 cells were also used to verify potential BBR mechanisms in neuroinflammation and microglial polarization. ResultsBBR improved cognitive performance, reduced amyloid pathology, and alleviated aberrant neuroinflammation in an AD mouse model. BBR induced microglial polarization to an M2-like phenotype, which was manifested by lowered and elevated proinflammatory and anti-inflammatory cytokine production, respectively, improved microglial uptake and Aβ clearance. Mechanistically, BBR directly interacted with TYROBP and promoted its activation by stabilizing TYROBP oligomerization. TYROBP knockdown aggravated M1-like polarization and pro-inflammatory gene expression in microglial cells in the presence of lipopolysaccharide (LPS)+Aβ, while blocked microglial M2-like polarization benefited from BBR administration. ConclusionsBBR modulated neuroinflammation by regulating microglial polarization via TYROBP activation. Our study provided new insight into BBR pharmacological actions in regulating microglial homeostasis and combating AD.

Nitric oxide donors rescue metabolic and mitochondrial dysfunction in obese Alzheimer’s model

Reduced nitric oxide (NO) bioavailability is a pathological link between obesity and Alzheimer’s disease (AD). Obesity-associated metabolic and mitochondrial bioenergetic dysfunction are key drivers of AD pathology. The hypothalamus is a critical brain region during the development of obesity and dysfunction is an area implicated in the development of AD. NO is an essential mediator of blood flow and mitochondrial bioenergetic function, but the role of NO in obesity-AD is not entirely clear. We investigated diet-induced obesity in female APPswe/PS1dE9 (APP) mouse model of AD, which we treated with two different NO donors (sodium nitrite or L-citrulline). After 26 weeks of a high-fat diet, female APP mice had higher adiposity, insulin resistance, and mitochondrial dysfunction (hypothalamus) than non-transgenic littermate (wild type) controls. Treatment with either sodium nitrite or L-citrulline did not reduce adiposity but improved whole-body energy expenditure, substrate oxidation, and insulin sensitivity. Notably, both NO donors restored hypothalamic mitochondrial respiration in APP mice. Our findings suggest that NO is an essential mediator of whole-body metabolism and hypothalamic mitochondrial function, which are severely impacted by the dual insults of obesity and AD pathology.

Amino Acid Compound 2 (AAC2) Treatment Counteracts Insulin-Induced Synaptic Gene Expression and Seizure-Related Mortality in a Mouse Model of Alzheimer’s Disease

Diabetes is a major risk factor for Alzheimer’s disease (AD). Amino acid compound 2 (AAC2) improves glycemic and cognitive functions in diabetic mouse models through mechanisms distinct from insulin. Our goal was to compare the effects of AAC2, insulin, and their nanofiber-forming combination on early asymptomatic AD pathogenesis in APP/PS1 mice. Insulin, but not AAC2 or the combination treatment (administered intraperitoneally every 48 h for 120 days), increased seizure-related mortality, altered the brain fat-to-lean mass ratio, and improved specific cognitive functions in APP/PS1 mice. NanoString and pathway analysis of cerebral gene expression revealed dysregulated synaptic mechanisms, with upregulation of Bdnf and downregulation of Slc1a6 in insulin-treated mice, correlating with insulin-induced seizures. In contrast, AAC2 promoted the expression of Syn2 and Syp synaptic genes, preserved brain composition, and improved survival. The combination of AAC2 and insulin counteracted free insulin’s effects. None of the treatments influenced canonical amyloidogenic pathways. This study highlights AAC2’s potential in regulating synaptic gene expression in AD and insulin-induced contexts related to seizure activity.

Fatty acid amide hydrolase gene inactivation induces hetero-cellular potentiation of microglial function in the 5xFAD mouse model of Alzheimer's disease.

Neuroinflammation has recently emerged as a crucial factor in Alzheimer's disease (AD) etiopathogenesis. Microglial cells play an important function in the inflammatory response; specifically, the emergence of disease-associated microglia (DAM) has offered new insights into the conflicting perspectives on the detrimental or beneficial roles of microglia. We previously showed that modulating the endocannabinoid tone by fatty acid amide hydrolase (FAAH) inactivation renders beneficial effects in an amyloidosis context, paradoxically accompanied by an exacerbated neuroinflammatory response and the enrichment of DAM population. Here, we aim to elucidate the role of microglial cells in FAAH-lacking mice in the 5xFAD mouse model of AD by using RNA-sequencing analysis, molecular determinations, and morphological studies by using in vivo multiphoton microscopy. FAAH-lacking AD mice displayed upregulated inflammatory genes and exhibited a DAM genetic profile. Conversely, genes linked to AD were downregulated. Depleting microglia using PLX5622 revealed that plaque-associated microglia in FAAH-deficient AD mice had a more stable, ramified morphology and increased Aβ uptake, leading to reduced plaque growth compared to control mice. Importantly, FAAH expression was negligible in microglial cells, thus suggesting a role for FAAH in the cellular interplay in the central nervous system. Our findings show that Faah gene inactivation triggers a hetero-cellular enhancement of microglial function that was paradoxically paralleled by an exacerbated inflammatory response. Taken together, the present data highlight FAAH as a potential therapeutic target in AD.

Effect of bioactive extracts from Eucalyptus globulus leaves in experimental models of Alzheimer's disease.

Current therapies for Alzheimer's disease (AD) do not delay its progression, therefore, novel disease-modifying strategies are urgently needed. Recently, an increasing number of compounds from natural origin with protective properties against AD have been identified. Mixtures or extracts obtained from natural products containing several bioactive compounds have multifunctional properties and have drawn the attention because multiple AD pathways can be simultaneously modulated. This study evaluated the in vitro and in vivo effect of the essential oil (EO) obtained from the hydrodistillation of Eucalyptus globulus leaves, and an extract obtained from the hydrodistillation residual water (HRW). It was observed that EO and HRW have anti-inflammatory effect in brain immune cells modeling AD, namely lipopolysaccharide (LPS)- and amyloid-beta (Aβ)-stimulated microglia. In cell models that mimic AD-related neuronal dysfunction, HRW attenuated Aβ secretion and Aβ-induced mitochondrial dysfunction. Since the HRW's major components did not cross the blood-brain barrier, both EO and HRW were administered to the APP/PS1 transgenic AD mouse model by an intranasal route, which reduced cortical and hippocampal Aβ levels, and to rescue memory deficits and anxiety-like behaviors. Finally, HRW and EO were found to regulate cholesterol levels in aged mice after intranasal administration, suggesting that these extracts can reduce hypercholesterolemia and avoid risk for AD development. Overall, findings support a protective role of E. globulus extracts against AD‑like pathology and cognitive impairment highlighting the underlying mechanisms. These extracts obtained from underused forest biomass could be useful to develop nutraceutical supplements helpful to avoid AD risk and to prevent its progression.

Gamma wave frequency affect Microglial states

Alzheimer’s disease (AD) is a chronic neurodegenerative disease, and its core symptoms are memory loss and cognitive impairment. Recent studies show that gamma wave oscillation plays an important role in regulating the protein level of starch and slowing down the progress of AD. This study focuses on the effect of gamma wave oscillation on the formation of amyloid spots in AD mouse model, and evaluates its possibility as a non-invasive treatment.

Gamma Wave Stimulation Affects BACE1 Levels and Promotes the Transition of Microglia from M1 State to M2 State

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and it presents with the hallmark neuropathological features of amyloid-beta (Aβ) plaques, tau tangles and active neuroinflammation. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), a key mediator of increased Aβ, has been identified as the primary enzymatic source for production of this pathologic peptide while reactive microglial cells contribute to ongoing neurodegeneration perhaps through activation into their aggressive M1 state. The present study endeavors for the first time to address how gamma wave stimulation modulates BACE1 and microglial polarization (from M1 to beneficial M2) in different AD models. We hypothesize that gamma wave stimulation will reduce BACE1, decrease Aβ plaque burden and shift microglials towards M2 phenotype leading to reduced neuroinflammation and maintain cognitive function. This study will target mouse models of AD which have undergone gamma wave stimulation and its effects on BACE1 expression, microglial polarisation markers, Aβ plaque load and cognitive performance. Hypotheses the treatment will reduce BACE1 activity, decrease M1/M2 microglial ratio, improve cognitive performance and delay Aβ plaque accumulation These data suggest promising therapeutic strategies for neuroinflammation and amyloidogenesis in AD.

Effects of Artemisia asiatica ex on Akkermansia muciniphila dominance for modulation of Alzheimer's disease in mice.

The gut microbiome influences neurological disorders through bidirectional communication between the gut and the brain, i.e., the gut-brain axis. Artemisia asiatica ex, an extract of Artemisia asiatica Nakai (Stillen®, DA-9601) has been reported to improve depression by increasing brain-derived neurotropic factor. Therefore, we hypothesized that DA-9601 can be a potential therapeutic candidate for Alzheimer's disease (AD) acting through the gut-brain axis. Four groups of Tg2576 mice were used as the animal model for AD: wild type mice (n = 6), AD mice (n = 6), and DA-9601-administered AD mice given dosages of 30mg/kg/day (DA_30mg; n = 6) or 100mg/kg/day (DA_100mg; n = 6). Microglial activation, blood‒brain barrier integrity, amyloid beta accumulation, cognitive behavior, and changes in the gut microbiome were analyzed. DA-9601 improved the cognitive behavior of mice (DA_30mg **p<0.01; DA_100mg **p<0.01) and reduced amyloid beta accumulation (DA_30mg ***p<0.001; DA_100mg **p<0.01). Increased Iba-1 and upregulation of claudin-5 (DA_30mg *p<0.05) and occludin (DA_30mg **p<0.01; DA_100mg ***p<0.001) indicated altered microglial activation and improved blood‒brain barrier integrity. Akkermansia muciniphila was dramatically increased by DA-9601 administration (DA_30mg 47%; DA_100mg 61%). DA-9601 improved AD pathology with Akkermansia muciniphila dominance in the gut microbiome in a mouse model of AD, inferring that DA-9601 can affect AD through the gut-brain axis.

Natural phenol carbamates: Selective BuChE/FAAH dual inhibitors show neuroprotection in an Alzheimer's disease mouse model

FAAH inhibition can indirectly enhance endocannabinoid signaling to therapeutic levels, effectively preventing or slowing its progression of Alzheimer's disease (AD). Hence, the search for effective dual FAAH/cholinesterase inhibitors is considerable need for disease-modifying therapies. To this aim, we designed, synthesized, and tested three series of natural phenol carbamates. The majority of carbamates proved to be potent on a single target, amongst them, compound D12 containing paeonol motif was identified as an effective dual BuChE/FAAH inhibitor, with well-balanced nanomolar activity (IC50 = 81 and 400 nM for hBuChE and hFFAH, respectively). D12 possessed BBB penetrating ability, benign safety, neuroprotection and pseudo-irreversible BuChE inhibition (Kd = 2.11 μM, k2 = 2.27 min−1), showing good drug-like properties. D12 also modulated the BV2 microglial polarization to inhibit neuroinflammation. In vivo study verified that D12 improved Aβ1-41-induced learning impairments in AD mouse model for both short- and long-term memory responses. Thus, the dual activity of D12 could lead to a potentially more effective treatment for the counteraction of AD progression.

Dihydro-resveratrol ameliorates NLRP3 inflammasome-mediated neuroinflammation via Bnip3-dependent mitophagy in Alzheimer's disease.

Dihydro-resveratrol (DHR), a polyphenol derivative, that has been demonstrated to suppress inflammation-mediated injury. However, it is still unknown whether it has anti-neuroinflammatory and neuroprotective effects, and a therapeutic action in Alzheimer's disease (AD). The anti-inflammatory and anti-Alzheimer's disease actions of dihydro-resveratrol were investigated using lipopolysaccharide (LPS) and AD mice models, and primary microglial cells. The changes in behaviour in mice were detected by the Morris water maze test and open-field test. Flow cytometry assay, western blotting, immunofluorescence assays and co-immunoprecipitation were used to investigate the changes in the NLRP3 inflammasome activation and mitophagy. In this study, in vivo observations indicated that the administration of dihydro-resveratrol (DHR) dramatically restored spatial learning, memory ability, autophagy and mitophagy, attenuated NLRP3 inflammasome activation, neuroinflammation and amyloid precursor protein pathology in LPS mice and AD mice. In addition, the inhibition of autophagy and mitophagy, or the activation of NLRP3 in vivo greatly abolished DHR-generated therapeutic efficacy on neuroinflammation, amyloid precursor protein pathology and cognitive loss. Further examination indicated that the application of DHR after the LPS and ATP exposure significantly inhibited the NLRP3 inflammasome activation, neuroinflammation and enhanced autophagic and mitophagic activation in microglia. Additionally, in vitro results show that DHR protects microglial cells against LPS and ATP-induced cytotoxicity by inhibiting NLRP3 inflammasome through activating Bnip3-dependent mitophagy and ULK phosphorylation. In summary, these findings suggest that dihydro-resveratrol (DHR) possesses potent anti-neuroinflammatory property and can act as a potential therapeutic agent for the treatment of AD.