Therapeutic Strategy For Alzheimer's Disease Research Articles

Inhibition of Fli‐1 attenuates inflammation, pericyte loss and cognitive deficits in Alzheimer’s disease

AbstractBackgroundBrain pericytes maintain the integrity of the blood‐brain barrier (BBB) and facilitate the removal of amyloid β (Aβ) which is critical to healthy brain activity (Ethan et al., Brain Pathol., 24: 371‐386, 2014). Pericyte degeneration has been observed in brains from patients with Alzheimer’s disease (AD) and animal models (Jesse et al., Brain Pathol., 23: 303‐10, 2013; Wu et al., Aging (Albany NY), 11: 6120‐6133, 2019). Our previous data demonstrated that friend leukemia virus integration 1 (Fli‐1), an ETS transcription factor, regulates pericyte viability and vascular injury in murine sepsis (Li et al., J Infect Dis, 218: 1995‐2005, 2018); however, the role of Fli‐1 in AD remains unknown.MethodsFli‐1 levels and pericyte number were detected in postmortem brains from 21 patients with AD and 17 healthy controls, and in 5xFAD transgenic mice. Control or Fli‐1 antisense oligonucleotide Gapmers were injected into the hippocampus of 5xFAD mice at 3 and 4.5 months of age. Pericyte number, inflammatory mediators, Aβ deposition, BBB function and cognitive deficits were evaluated at 6 months of age. Human brain pericytes were transfected with control or Fli‐1 antisense Gapmers for 48 h and cultured with or without freshly aggregated Aβ40 for 7 consecutive days. Cell viability and apoptosis were detected.ResultsWe demonstrated that Fli‐1 expression was increased in postmortem brains from a cohort of human AD donors and in 5xFAD mice, which corresponded with a decreased pericyte number, elevated inflammatory mediators, and increased Aβ accumulation as compared to cognitively normal individuals and WT mice, respectively. Antisense oligonucleotide Fli‐1 Gapmer administrated via intrahippocampal injection decelerated pericyte loss, reduced inflammatory responses, ameliorated cognitive deficits, improved BBB dysfunction, and decreased Aβ deposition in 5xFAD mice. Fli‐1 Gapmer‐mediated inhibition of Fli‐1 protected against Aβ accumulation induced human brain pericyte apoptosis in vitro.ConclusionThese composite results indicate that Fli‐1 contributes to pericyte loss, inflammatory response, Aβ deposition, vascular dysfunction and cognitive decline, and suggest that suppression of Fli‐1 may represent a novel therapeutic strategy for AD.

Sex‐specific accumulation and therapeutic effect of the histone variant H2A.Z in Alzheimer’s disease

AbstractBackgroundThere is growing evidence that dysregulation of gene expression plays a role in cognitive deficits and neuropathology in Alzheimer’s disease (AD), thus prompting interest in epigenetic factors as mechanisms of neurodegeneration and memory loss. Here, we assess the therapeutic potential of the histone variant H2A.Z. H2A.Z is a memory suppressor that is actively removed from DNA during learning to promote gene expression and memory formation. The memory‐suppressive effects of H2A.Z are further supported by our finding that H2A.Z levels increase in the aged brain and may act as a prelude to age‐related memory decline. We hypothesize that H2A.Z also accumulates in AD and that targeted depletion of H2A.Z is an effective therapy for memory impairment.MethodsTo characterize H2A.Z levels in the AD brain, we assessed genome wide (ChIP‐seq) and site‐specific (ChIP‐qPCR) binding of H2A.Z to DNA as well as mRNA expression of genes encoding H2A.Z in both the human post‐mortem and 5xFAD mouse hippocampus. To directly test the therapeutic potential of H2A.Z depletion, adeno‐associated virus (AAV) vector containing short hairpin RNA against H2A.Z was delivered in the hippocampus of 5xFAD mice and memory was assessed using object location and contextual fear conditioning tasks.ResultsConsistent with the hypothesis that H2A.Z accumulates in the AD brain, binding of H2A.Z increased at several memory and AD‐related genes in the human and 5xFAD female hippocampus. Interestingly, this effect was sex specific, as H2A.Z binding decreased in the male hippocampus across species. Similarly, mRNA expression of genes encoding H2A.Z increased in the human and 5xFAD female hippocampus. This female‐specific increase in H2A.Z was paralleled by the remediation of memory impairment following H2A.Z depletion in 5xFAD females but not males.ConclusionOur data are the first demonstration of histone variants as regulators of AD‐related memory impairment. The sex‐specific changes in H2A.Z generalize across species and provide promising support for H2A.Z depletion as a therapeutic strategy for AD in females.

Reactive Sulfur Species Omics Analysis in the Brain Tissue of the 5xFAD Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder whereby oxidative stress augmentation results in mitochondrial dysfunction and cell death by apoptosis. Emerging evidence indicates that reactive sulfur species (RSS), such as glutathione hydropersulfide (GSSH), is endogenously produced, functions as potent antioxidants, and regulate redox signaling through the formation of protein polysulfides. However, the relationship between RSS and AD pathogenesis is not fully understood. In this study, we analyzed endogenous RSS production in the brain tissue of a familial AD model (5xFAD) mouse using multiple RSS-omics approaches. Memory impairment, increased amyloid plaques, and neuroinflammation have been confirmed in 5xFAD mice. Quantitative RSS omics analysis revealed that the total polysulfide content was significantly decreased in the brains of 5xFAD mice, whereas there was no significant difference in the levels of glutathione, GSSH, or hydrogen sulfide between wild-type and 5xFAD mice. In contrast, a significant decline in the protein polysulfide status was observed in the brains of 5xFAD mice, suggesting that RSS production and subsequent redox signaling might be altered during the onset and progression of AD. Our findings have important implications for understanding the significance of RSS in the development of preventive and therapeutic strategies for AD.

Plasmon-activated water as a therapeutic strategy in Alzheimer's disease by altering gut microbiota.

Gut microbiota (GM) are involved in the pathophysiology of Alzheimer's disease (AD) and might correlate to the machinery of the gut-brain axis. Alteration of the GM profiles becomes a potential therapy strategy in AD. Here, we found that plasmon-activated water (PAW) therapy altered GM profile and reduced AD symptoms in APPswe/PS1dE9 transgenic mice (AD mice). GM profile showed the difference between AD and WT mice. PAW therapy in AD mice altered GM profile and fecal microbiota transplantation (FMT) reproduced GM profile in AD mice. PAW therapy and FMT in AD mice reduced cognitive decline and amyloid accumulation by novel object recognition (NOR) test and amyloid PET imaging. Immunofluorescent staining and western blot analysis of β-amyloid (Aβ) and phosphorylated (p)-tau in the brain of AD mice were reduced in PAW therapy and FMT. The inflammatory markers, interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α and pro-inflammatory indicator of arginase-1/CD86 ratio were also reduced. Furthermore, immunohistochemistry (IHC) analysis of occludin and claudin-5 in the intestine and AXL in the brain were increased to correlate with the abundant GM in PAW therapy and FMT. Our results showed the machinery of gut-brain axis, and PAW might be a potential therapeutic strategy in AD.

The Functions and Phenotypes of Microglia in Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide, but therapeutic strategies to slow down AD pathology and symptoms have not yet been successful. While attention has been focused on neurodegeneration in AD pathogenesis, recent decades have provided evidence of the importance of microglia, and resident immune cells in the central nervous system. In addition, new technologies, including single-cell RNA sequencing, have revealed heterogeneous cell states of microglia in AD. In this review, we systematically summarize the microglial response to amyloid-β and tau tangles, and the risk factor genes expressed in microglia. Furthermore, we discuss the characteristics of protective microglia that appear during AD pathology and the relationship between AD and microglia-induced inflammation during chronic pain. Understanding the diverse roles of microglia will help identify new therapeutic strategies for AD.

Brain p3‐Alcβ peptide restores neuronal viability impaired by Alzheimer's amyloid β‐peptide

We propose a new therapeutic strategy for Alzheimer's disease (AD). Brain peptide p3‐Alcβ37 is generated from the neuronal protein alcadein β through cleavage of γ‐secretase, similar to the generation of amyloid β (Aβ) derived from Aβ‐protein precursor/APP. Neurotoxicity by Aβ oligomers (Aβo) is the prime cause prior to the loss of brain function in AD. We found that p3‐Alcβ37 and its shorter peptide p3‐Alcβ9‐19 enhanced the mitochondrial activity of neurons and protected neurons against Aβo‐induced toxicity. This is due to the suppression of the Aβo‐mediated excessive Ca2+ influx into neurons by p3‐Alcβ. Successful transfer of p3‐Alcβ9‐19 into the brain following peripheral administration improved the mitochondrial viability in the brain of AD mice model, in which the mitochondrial activity is attenuated by increasing the neurotoxic human Aβ42 burden, as revealed through brain PET imaging to monitor mitochondrial function. Because mitochondrial dysfunction is common in the brain of AD patients alongside increased Aβ and reduced p3‐Alcβ37 levels, the administration of p3‐Alcβ9‐19 may be a promising treatment for restoring, protecting, and promoting brain functions in patients with AD.

The impact of selective and non-selective medial septum stimulation on hippocampal neuronal oscillations: A study based on modeling and experiments

Alzheimer's disease (AD) is a neurodegenerative disorder with a rising socioeconomic impact on societies. The hippocampus (HPC), which plays an important role in AD, is affected in the early stages. The medial septum (MS) in the forebrain provides major cholinergic input to the HPC and has been shown to play a significant role in generating oscillations in hippocampal neurons. Cholinergic neurons in the basal forebrain are particularly vulnerable to neurodegeneration in AD. To better understand the role of MS neurons including the cholinergic, glutamatergic, and GABAergic subpopulations in generating the well-known brain rhythms in HPC including delta, theta, slow gamma, and fast gamma oscillations, we designed a detailed computational model of the septohippocampal pathway. We validated the results of our model, using electrophysiological recordings in HPC with and without stimulation of the cholinergic neurons in MS using designer receptors exclusively activated by designer drugs (DREADDs) in healthy male ChAT-cre rats. Then, we eliminated 75% of the MS cholinergic neurons in the model to simulate degeneration in AD. A series of selective and non-selective stimulations of the remaining MS neurons were performed to understand the dynamics of oscillation regulation in the HPC during the degenerated state. In this way, appropriate stimulation strategies able to normalize the aberrant oscillations are proposed. We found that selectively stimulating the remaining healthy cholinergic neurons was sufficient for network recovery and compare this to stimulating other subpopulations and a non-selective stimulation of all MS neurons. Our data provide valuable information for the development of new therapeutic strategies in AD and a tool to test and predict the outcome of potential theranostic manipulations.

Peptoids as potential therapeutics to reduce S100B-induced RAGE-associatedneuroinflammation in Alzheimer's disease.

Receptor for advanced glycation end-products (RAGE)-associated chronic neuroinflammation has been linked with Alzheimer's disease (AD) pathology. RAGE ligand S100B, which is elevated in AD brain, can induce release of inflammatory cytokines and upregulate RAGE. Consequently, targeting RAGE to reduce chronic inflammation represents a novel therapeutic strategy for AD. Peptoids are ideal potential AD therapeutics as they resist proteolytic degradation by repositioning side-chains from the α-carbon to the amide nitrogen and exhibit facile blood-brain barrier permeability. Peptoids designed to mimic RAGE ligands demonstrated strong binding affinity to RAGE in our previous studies. We hypothesize that these peptoids can attenuate S100B-induced activation of RAGE, thus reducing pro-inflammatory cytokine release associated with chronic neuroinflammation. Differentiated THP-1 macrophages were exposed to chronic low-levels of S100B to confirm upregulation of cytokine release. Macrophages were then treated with 0-50-μM peptoids (JPT1 or JPT1a) in the presence of S100B. To observe peptoid modulation of S100B-induced inflammation, cytokine analysis via immunoassay was performed using cell culture supernatants. Additionally, RAGE was incubated in the presence of 0-500-nM peptoid to achieve equilibrium. Unbound RAGE was quantified via modified ELISA to determine the binding affinity. S100B-treated THP-1 macrophages elicited anticipated inflammatory response evidenced by dose-dependent upregulation of cytokines. When THP-1 macrophages were incubated with peptoids and S100B, peptoids attenuated these S100B-induced inflammatory responses. Moreover, the peptoids demonstrated nanomolar binding affinity for RAGE. Peptoids modulate inflammatory responses induced by RAGE ligand S100B, including inflammatory cytokine release. These results implicate peptoids as a potential therapeutic agent for not only AD but also other inflammation-related illnesses. Because these peptoids have additionally exhibited the ability to modulate Aβ aggregation and transform the morphology of the aggregates formed, they may function as dual-target therapeutics for AD.

Stabilization of Monomeric Tau Protein by All D-Enantiomeric Peptide Ligands as Therapeutic Strategy for Alzheimer's Disease and Other Tauopathies.

Alzheimer's disease and other tauopathies are the world's leading causes of dementia and memory loss. These diseases are thought to be caused by the misfolding and aggregation of the intracellular tau protein, ultimately leading to neurodegeneration. The tau protein is involved in a multitude of different neurodegenerative diseases. During the onset of tauopathies, tau undergoes structural changes and posttranslational modifications and aggregates into amyloid fibrils that are able to spread with a prion-like behavior. Up to now, there is no therapeutic agent which effectively controls or reverses the disease. Most of the therapeutics that were developed and underwent clinical trials targeted misfolded or aggregated forms of tau. In the current manuscript, we present the selection and characterization of two all D-enantiomeric peptides that bind monomeric tau protein with a low nanomolar KD, stabilize tau in its monomeric intrinsically disordered conformation, and stop the conversion of monomers into aggregates. We show that the effect of the two all D-enantiomeric peptides is strong enough to stop ongoing tau aggregation in vitro and is able to significantly reduce tau fibril assembly in cell culture. Both compounds may serve as new lead components for the development of therapeutic agents against Alzheimer's disease and other tauopathies.

The Amyloid Cascade Hypothesis 2.0: Generalization of the Concept.

Recently, we proposed the Amyloid Cascade Hypothesis 2.0 (ACH2.0), a reformulation of the ACH. In the former, in contrast to the latter, Alzheimer's disease (AD) is driven by intraneuronal amyloid-β (iAβ) and occurs in two stages. In the first, relatively benign stage, Aβ protein precursor (AβPP)-derived iAβ activates, upon reaching a critical threshold, the AβPP-independent iAβ-generating pathway, triggering a devastating second stage resulting in neuronal death. While the ACH2.0 remains aligned with the ACH premise that Aβ is toxic, the toxicity is exerted because of intra- rather than extracellular Aβ. In this framework, a once-in-a-lifetime-only iAβ depletion treatment via transient activation of BACE1 and/or BACE2 (exploiting their Aβ-cleaving activities) or by any means appears to be the best therapeutic strategy for AD. Whereas the notion of differentially derived iAβ being the principal moving force at both AD stages is both plausible and elegant, a possibility remains that the second AD stage is enabled by an AβPP-derived iAβ-activated self-sustaining mechanism producing a yet undefined deleterious "substance X" (sX) which anchors the second AD stage. The present study generalizes the ACH2.0 by incorporating this possibility and shows that, in this scenario, the iAβ depletion therapy may be ineffective at symptomatic AD stages but fully retains its preventive potential for both AD and the aging-associated cognitive decline, which is defined in the ACH2.0 framework as the extended first stage of AD.

Early-stage Alzheimer's disease: are skeletal muscle and exercise the key?

Alzheimer's disease (AD) is the most common form of dementia affecting approximately 6.5 million people in the United States alone. The development of AD progresses over a span of years to possibly decades before resulting in cognitive impairment and clinically diagnosed AD. The time leading up to a clinical diagnosis is known as the preclinical phase, a time in which recent literature has noted a more severe loss of body mass and more specifically lean muscle mass and strength prior to diagnosis. Mitochondria dysfunction in neurons is also closely associated with AD, and mitochondrial dysfunction has been seen to occur in skeletal muscle with mild cognitive impairment prior to AD manifestation. Evidence from animal models of AD suggests a close link among skeletal muscle mass, mitochondria function, and cognition. Exercise is a powerful stimulus for improving mitochondria function and muscle health, and its benefits to cognition have been suggested as a possible therapeutic strategy for AD. However, evidence for beneficial effects of exercise in AD-afflicted populations and animal models has produced conflicting results. In this mini-review, we discuss these findings and highlight potential avenues for further investigation that may lead to the implementation of exercise as a therapeutic intervention to delay or prevent the development of AD.

Analysis of Aβ-induced neurotoxicity and microglial responses in simple two- and three-dimensional human iPSC-derived cortical culture systems

The extracellular accumulation of amyloid-β (Aβ) in plaques and associated neurodegeneration are the pathological hallmarks of Alzheimer’s disease (AD). These plaques are surrounded by microglia—the resident tissue macrophages of the brain parenchyma that originate from primitive macrophages from the embryonic yolk sac. Microglia, including a unique subpopulation called “disease-associated microglia” (DAM), are strongly implicated in AD pathology; however, their exact function and physiology remain largely unknown. Notably, simple cell and tissue culture systems that adequately recreate the brain microenvironment and can simulate critical aspects of AD pathology could fundamentally contribute to elucidating microglial function in disease development and progression. Thus, we added human-induced pluripotent stem cell (hiPSC)-induced primitive macrophages (hiMacs) to hiPSC-induced cortical neurons (cell model) and cortical organoids (tissue model). The treatment of these culture systems with the O-acyl isopeptide of Aβ1−42, which reverts to natural extracellular Aβ1−42 at neutral pH and starts self-aggregation, caused the degeneration of hiPSC-induced cortical neurons in 2D culture and within cortical organoid cultures. Notably, the hiMacs phagocytosed extracellular Aβ and exhibited a DAM-like phenotype. In both cell and tissue organoid culture systems, neurodegeneration was attenuated by the addition of hiMacs. Moreover, in cortical organoids, Aβ plaques formed more circular and fewer hotspot-like morphological structures in the vicinity of hiMacs. These findings demonstrate the utility of simple hiPSC-induced cortical cell and tissue culture systems supplemented with hiMacs for elucidating critical aspects of AD pathology, such as microglial function and physiology. Adopting such systems in routine research practice may lead to the development of novel therapeutic strategies for AD.

Evolutionarily conserved regulators of tau identify targets for new therapies

Tauopathies are neurodegenerative diseases that involve the pathological accumulation of tau proteins; in this family are Alzheimer disease, corticobasal degeneration, and chronic traumatic encephalopathy, among others. Hypothesizing that reducing this accumulation could mitigate pathogenesis, we performed a cross-species genetic screen targeting 6,600 potentially druggable genes in human cells and Drosophila. We found and validated 83 hits in cells and further validated 11 hits in the mouse brain. Three of these hits (USP7, RNF130, and RNF149) converge on the C terminus of Hsc70-interacting protein (CHIP) to regulate tau levels, highlighting the role of CHIP in maintaining tau proteostasis in the brain. Knockdown of each of these three genes in adult tauopathy mice reduced tau levels and rescued the disease phenotypes. This study thus identifies several points of intervention to reduce tau levels and demonstrates that reduction of tau levels via regulation of this pathway is a viable therapeutic strategy for Alzheimer disease and other tauopathies.

Identification of a dual Aβ‐tau disaggregator for the treatment of Alzheimer’s disease

AbstractBackgroundThe accumulation of misfolded protein aggregates is connected with neurodegenerative diseases such as Alzheimer’s disease (AD), and Parkinson’s disease. Because of the accumulation of amyloid β (Aβ) plaques and tau tangles (NFTs) in the brain, neurons slowly degenerate and lose their functions in AD. Recently, many clinical trials for AD therapy with single‐target drugs, especially targeted for Aβ or tau aggregates, have failed. As a therapeutic strategy for AD, we therefore propose to introduce a multifunctional anti‐AD agent to disaggregate the Aβ plaques and NFTs.MethodHit compound was selected with disaggregation of Aβ and tau aggregates in various concentrations and half maximal effective concentration by thioflavin T (ThT) fluorescence assay. In vitro study, we examined the effects of our hit compound on the accumulation of intracellular Aβ or tau in over‐expressing cells. In vivo study, we administrated orally our hit compound to AD mouse model for 12 weeks (100mg/kg by weekly). Analysis of Aβ and tau was performed by molecular biological and histological experiments.ResultOur results show that the hit compound had dual disaggregation capacity for Aβ and tau aggregates. We observed significant decrease of Aβ and NFTs in hit compound treated AD mice compared to vehicle treated. Also, we found the restoration of cognitive decline in compound treated AD mice.ConclusionThe study demonstrate that our hit compound was identified as dual functional drug for Aβ and NFTs disaggregator. These findings may help to design the next generations of dual or selective disaggregators.

Inhibiting tyrosine kinase c‐KIT as a therapeutic strategy for Alzheimer’s Disease

AbstractBackgroundImpaired autophagy and neuroinflammation, two primary features of Alzheimer’s Disease, were examined as potential pharmacological targets for alleviating amyloid‐beta and tau burden using novel tyrosine kinase inhibitors.MethodTransgenic APP mice were treated for 6 weeks with either one of two novel tyrosine kinase inhibitors or DMSO (n = 10) before having their behavior tested on the novel object recognition test, the Morris water maze, and the elevated plus maze. Brain samples were then extracted and probed for levels of amyloid‐beta, tau, and autophagic machinery, as well as numbers of mast cells and microglia using ELISA, immunohistochemistry, and flow cytometry.ResultMice treated with our novel tyrosine kinase inhibitors exhibited robust improvements on behavioral measures. These treated mice displayed concurrent decreases in levels of amyloid‐beta and tau, as well as increased levels of autophagic machinery and decreased numbers of microglia and mast cells.ConclusionTyrosine kinase inhibition represents a valid mechanism for improving autophagic clearance of neurotoxic protein and mitigating mast cell and microglial‐mediated inflammation, identifying this method as a potential target for therapeutic intervention for treating Alzheimer’s Disease.

Identification of Novel Kinases of Tau Using Fluorescence Complementation Mass Spectrometry (FCMS)

Hyperphosphorylation of the microtubule-associated protein Tau is a major hallmark of Alzheimer's disease and other tauopathies. Understanding the protein kinases that phosphorylate Tau is critical for the development of new drugs that target Tau phosphorylation. At present, the repertoire of the Tau kinases remains incomplete, and methods to uncover novel upstream protein kinases are still limited. Here, we apply our newly developed proteomic strategy, fluorescence complementation mass spectrometry, to identify novel kinase candidates of Tau. By constructing Tau- and kinase-fluorescent fragment library, we detected 59 Tau-associated kinases, including 23 known kinases of Tau and 36 novel candidate kinases. In the validation phase using invitro phosphorylation, among 15 candidate kinases we attempted to purify and test, four candidate kinases, OXSR1 (oxidative-stress responsive gene 1), DAPK2 (death-associated protein kinase 2), CSK (C-terminal SRC kinase), and ZAP70 (zeta chain of T-cell receptor-associated protein kinase 70), displayed the ability to phosphorylate Tau in time-course experiments. Furthermore, coexpression of these four kinases along with Tau increased the phosphorylation of Tau in human neuroglioma H4 cells. We demonstrate that fluorescence complementation mass spectrometry is a powerful proteomic strategy to systematically identify potential kinases that can phosphorylate Tau in cells. Our discovery of new candidate kinases of Tau can present new opportunities for developing Alzheimer's disease therapeutic strategies.

Miltefosine as a PPM1A activator improves AD-like pathology in mice by alleviating tauopathy via microglia/neurons crosstalk

Alzheimer's disease (AD) is a progressively neurodegenerative disease without effective treatment. Here, we reported that the levels of expression and enzymatic activity of phosphatase magnesium-dependent 1A (PPM1A) were both repressed in brains of AD patient postmortems and 3 × Tg-AD mice, and treatment of adeno-associated virus (AAV)-ePHP-overexpression (OE)-PPM1A for brain-specific PPM1A overexpression or the new discovered PPM1A activator Miltefosine (MF, FDA approved oral anti-leishmanial drug) for PPM1A enzymatic activation improved the AD-like pathology in 3 × Tg-AD mice. The mechanism was intensively investigated by assay against the 3 × Tg-AD mice with brain-specific PPM1A knockdown (KD) through AAV-ePHP-KD-PPM1A injection. MF alleviated neuronal tauopathy involving microglia/neurons crosstalk by both promoting microglial phagocytosis of tau oligomers via PPM1A/Nuclear factor-κb (NF-κB)/C-X3-C Motif Chemokine Receptor 1 (CX3CR1) signaling and inhibiting neuronal tau hyperphosphorylation via PPM1A/NLR Family Pyrin Domain Containing 3 (NLRP3)/tau axis. MF suppressed microglial NLRP3 inflammasome activation by both inhibiting NLRP3 transcription via PPM1A/NF-κB/NLRP3 pathway in priming step and promoting PPM1A binding to NLRP3 to interfere NLRP3 inflammasome assembly in assembly step. Our results have highly addressed that PPM1A activation shows promise as a therapeutic strategy for AD and highlighted the potential of MF in treating this disease.

Blood Cerebrospinal Fluid Barrier Function Disturbance Can Be Followed by Amyloid-β Accumulation.

Background: Elucidation of the mechanism of amyloid-β accumulation plays an important role in therapeutic strategies for Alzheimer’s disease (AD). The aim of this study is to elucidate the relationship between the function of the blood–cerebrospinal fluid barrier (BCSFB) and the clearance of amyloid-β (Aβ). Methods: Twenty-five normal older adult volunteers (60–81 years old) participated in this PET study for clarifying the relationship between interstitial water flow and Aβ accumulation. Water dynamics were analyzed using two indices in [15O]H2O PET, the influx ratio (IR) and drain rate (DR), and Aβ accumulation was assessed qualitatively by [18F]flutemetamol PET. Results: [15O]H2O PET examinations conducted initially and after 2 years showed no significant changes in both indices over the 2-year period (IR: 1.03 ± 0.21 and 1.02 ± 0.20, DR: 1.74 ± 0.43 and 1.67 ± 0.47, respectively). In [18F]flutemetamol PET, on the other hand, one of the 25 participants showed positive results and two showed positive changes after 2 years. In these three participants, the two indices of water dynamics showed low values at both periods (IR: 0.60 ± 0.15 and 0.60 ± 0.13, DR: 1.24 ± 0.12 and 1.11 ± 0.10). Conclusions: Our results indicated that BCSFB function disturbances could be followed by Aβ accumulation, because the reduced interstitial flow preceded amyloid accumulation in the positive-change subjects, and amyloid accumulation was not observed in the older adults with sufficiently high values for the two indices. We believe that further elucidation of interstitial water flow will be the key to developing therapeutic strategies for AD, especially with regard to prevention.

Activation of β2-adrenergic Receptor Ameliorates Amyloid-β-induced Mitophagy Defects and Tau Pathology in Mice

Defective mitophagy and mitochondrial dysfunction have been linked to aging and Alzheimer’s disease (AD). β2-Adrenergic receptor (ADRB2) is critical for mitochondrial and cognitive function. However, researchers have not clearly determined whether ADRB2 activation ameliorates defective mitophagy and cognitive deficits in individuals with AD. Here, we observed that the activation of ADRB2 by clenbuterol (Clen, ADRB2 agonist, 2 mg/kg/day) ameliorated amyloid-β-induced (Aβ1-42 bilateral intracerebral infusion, 2 μl, 5 μg/μl) memory deficits. Activation of ADRB2 also attenuated Aβ-induced mitochondrial dysfunction, as revealed by increased ATP levels, mitochondrial membrane potential (MMP/Δψm) and complex I activity. Further studies revealed that ADRB2 activation restored mitophagy deficits, as revealed by the increased light chain 3 (LC3)-II/LC3-I ratio, Atg5 levels, and Atg7 levels and decreased p62 levels, along with the upregulation of PTEN-induced putative kinase 1 (PINK1), Parkin and NAD+ levels. Activation of ADRB2 rescued Aβ-induced oxidative stress and neuronal death. ADRB2 activation also attenuated Aβ-induced tau hyperphosphorylation by regulating glycogen synthase kinase-3β expression in the hippocampus. Finally, we established that Clen improved mitophagy and attenuated mitochondrial dysfunction, and tau pathology in mice by activating the ADRB2/Akt/PINK1 signaling pathway. Conversely, the inhibition of ADRB2 by propranolol (βAR antagonist, 10 μM) blocked the Clen-mediated improvements in pathological changes in N2a cells. The results from the present study indicate that ADRB2 activation may be a therapeutic strategy for AD.

The Gut Microbiome and Alzheimer's Disease: A Growing Relationship.

Evidence that the gut microbiota plays a key role in the pathogenesis of Alzheimer's disease is already unravelling. The microbiota-gut-brain axis is a bidirectional communication system that is not fully understood but includes neural, immune, endocrine, and metabolic pathways. The progression of Alzheimer's disease is supported by mechanisms related to the imbalance in the gut microbiota and the development of amyloid plaques in the brain, which are at the origin of Alzheimer's disease. Alterations in the composition of the gut microbiome led to dysregulation in the pathways governing this system. This leads to neurodegeneration through neuroinflammation and neurotransmitter dysregulation. Neurodegeneration and disruption of the blood-brain barrier are frontiers at the origin of Alzheimer's disease. Furthermore, bacteria populating the gut microbiota can secrete large amounts of amyloid proteins and lipopolysaccharides, which modulate signaling pathways and alter the production of proinflammatory cytokines associated with the pathogenesis of Alzheimer's disease. Importantly, through molecular mimicry, bacterial amyloids may elicit cross-seeding of misfolding and induce microglial priming at different levels of the brain-gut-microbiota axis. The potential mechanisms of amyloid spreading include neuron-to-neuron or distal neuron spreading, direct blood-brain barrier crossing, or via other cells such as astrocytes, fibroblasts, microglia, and immune system cells. Gut microbiota metabolites, including short-chain fatty acids, pro-inflammatory factors, and neurotransmitters may also affect AD pathogenesis and associated cognitive decline. The purpose of this review is to summarize and discuss the current findings that may elucidate the role of gut microbiota in the development of Alzheimer's disease. Understanding the underlying mechanisms may provide new insights into novel therapeutic strategies for Alzheimer's disease, such as probiotics and targeted oligosaccharides.