Therapeutic Strategy For Alzheimer's Disease Research Articles

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.

Isorhamnetin Attenuated the Release of Interleukin-6 from β-Amyloid-Activated Microglia and Mitigated Interleukin-6-Mediated Neurotoxicity.

Alzheimer's disease (AD), characterized by the abnormal accumulation of β-amyloid (Aβ), is the most prevalent type of dementia, and it is associated with progressive cognitive decline and memory loss. Aβ accumulation activates microglia, which secrete proinflammatory factors associated with Aβ clearance impairment and cause neurotoxicity, generating a vicious cycle among Aβ accumulation, activated microglia, and proinflammatory factors. Blocking this cycle can be a therapeutic strategy for AD. Using Aβ-activated HMC3 microglial cells, we observed that isorhamnetin, a main constituent of Oenanthe javanica, reduced the Aβ-triggered secretion of interleukin- (IL-) 6 and downregulated the expression levels of the microglial activation markers ionized calcium binding adaptor molecule 1 (IBA1) and CD11b and the inflammatory marker nuclear factor-κB (NF-κB). Treatment of the SH-SY5Y-derived neuronal cells with the Aβ-activated HMC3-conditioned medium (HMC3-conditioned medium) or IL-6 increased reactive oxygen species production, upregulated cleaved caspase 3 expression, and reduced neurite outgrowth, whereas treatment with isorhamnetin counteracted these neurodegenerative presentations. In the SH-SY5Y-derived neuronal cells, IL-6 upregulated the phosphorylation of tyrosine kinase 2 (TYK2) and signal transducer and activator of transcription 1 (STAT1), whereas isorhamnetin normalized this abnormal phosphorylation. Overexpression of TYK2 attenuated the neuroprotective effect of isorhamnetin on IL-6-induced neurotoxicity. Our findings demonstrate that isorhamnetin exerts its neuroprotective effect by mediating the neuroinflammatory IL-6/TYK2 signaling pathway, suggesting its potential for treating AD.

Elevating microglia TREM2 reduces amyloid seeding and suppresses disease-associated microglia.

TREM2 is exclusively expressed by microglia in the brain and is strongly linked to the risk for Alzheimer's disease (AD). As microglial responses modulated by TREM2 are central to AD pathogenesis, enhancing TREM2 signaling has been explored as an AD therapeutic strategy. However, the effective therapeutic window targeting TREM2 is unclear. Here, by using microglia-specific inducible mouse models overexpressing human wild-type TREM2 (TREM2-WT) or R47H risk variant (TREM2-R47H), we show that TREM2-WT expression reduces amyloid deposition and neuritic dystrophy only during the early amyloid seeding stage, whereas TREM2-R47H exacerbates amyloid burden during the middle amyloid rapid growth stage. Single-cell RNA sequencing reveals suppressed disease-associated microglia (DAM) signature and reduced DAM population upon TREM2-WT expression in the early stage, whereas upregulated antigen presentation pathway is detected with TREM2-R47H expression in the middle stage. Together, our findings highlight the dynamic effects of TREM2 in modulating AD pathogenesis and emphasize the beneficial effect of enhancing TREM2 function in the early stage of AD development.

Toll-Like Receptor 4: A Promising Therapeutic Target for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that primarily manifests as memory deficits and cognitive impairment and has created health challenges for patients and society. In AD, amyloid β-protein (Aβ) induces Toll-like receptor 4 (TLR4) activation in microglia. Activation of TLR4 induces downstream signaling pathways and promotes the generation of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), which also trigger the activation of astrocytes and influence amyloid-dependent neuronal death. Therefore, TLR4 may be an important molecular target for treating AD by regulating neuroinflammation. Moreover, TLR4 regulates apoptosis, autophagy, and gut microbiota and is closely related to AD. This article reviews the role of TLR4 in the pathogenesis of AD and a range of potential therapies targeting TLR4 for AD. Elucidating the regulatory mechanism of TLR4 in AD may provide valuable clues for developing new therapeutic strategies for AD.

Adiponectin, the adiponectin paradox, and Alzheimer's Disease: Is this association biologically plausible?

Dementia, especially Alzheimer's Disease (AD) and vascular dementia, is a major public health problem that continues to expand in both economically emerging and hegemonic countries. In 2017, the World Alzheimer Report estimated that over 50 million people were living with dementia globally. Metabolic dysfunctions of brain structures such as the hippocampus and cerebral cortex have been implicated as risk factors for dementia. Several well-defined metabolic risk factors for AD include visceral obesity, chronic inflammation, peripheral and brain insulin resistance, type 2 diabetes mellitus (T2DM), hypercholesterolemia, and others. In this review, we describe the relationship between the dysmetabolic mechanisms, although still unknown, and dementia, particularly AD. Adiponectin (ADPN), the most abundant circulating adipocytokine, acts as a protagonist in the metabolic dysfunction associated with AD, with unexpected and intriguing dual biological functions. This contradictory role of ADPN has been termed the adiponectin paradox. Some evidence suggests that the adiponectin paradox is important in amyloidogenic evolvability in AD. We present cumulative evidence showing that AD and T2DM share many common features. We also review the mechanistic pathways involving brain insulin resistance. We discuss the importance of the evolvability of amyloidogenic proteins (APs), defined as the capacity of a system for adaptive evolution. Finally, we describe potential therapeutic strategies in AD, based on the adiponectin paradox.

MiR-143-3p Inhibits Aberrant Tau Phosphorylation and Amyloidogenic Processing of APP by Directly Targeting DAPK1 in Alzheimer’s Disease

The neuropathology of Alzheimer’s disease (AD) is characterized by intracellular aggregation of hyperphosphorylated tau and extracellular accumulation of beta-amyloid (Aβ). Death-associated protein kinase 1 (DAPK1), as a novel therapeutic target, shows promise for the treatment of human AD, but the regulatory mechanisms of DAPK1 expression in AD remain unclear. In this study, we identified miR-143-3p as a promising candidate for targeting DAPK1. miR-143-3p directly bound to the 3′ untranslated region of human DAPK1 mRNA and inhibited its translation. miR-143-3p decreased tau phosphorylation and promoted neurite outgrowth and microtubule assembly. Moreover, miR-143-3p attenuated amyloid precursor protein (APP) phosphorylation and reduced the generation of Aβ40 and Aβ42. Furthermore, restoring DAPK1 expression with miR-143-3p antagonized the effects of miR-143-3p in attenuating tau hyperphosphorylation and Aβ production. In addition, the miR-143-3p levels were downregulated and correlated inversely with the expression of DAPK1 in the hippocampus of AD patients. Our results suggest that miR-143-3p might play critical roles in regulating both aberrant tau phosphorylation and amyloidogenic processing of APP by targeting DAPK1 and thus offer a potential novel therapeutic strategy for AD.

Elevated levels of tripeptidyl peptidase 1 do not ameliorate pathogenesis in a mouse model of Alzheimer disease

One potential therapeutic strategy for Alzheimer disease (AD) is to promote degradation of amyloid beta (Aβ) and we previously demonstrated that the lysosomal protease tripeptidyl peptidase 1 (TPP1) can degrade Aβ fibrils in vitro. In this study, we tested the hypothesis that increasing levels of TPP1 might promote degradation of Aβ under physiological conditions, slowing or preventing its accumulation in the brain with subsequent therapeutic benefits. We used 2 approaches to increase TPP1 activity in the brain of J20 mice, an AD model that accumulates Aβ and exhibits cognitive defects: transgenic overexpression of TPP1 in the brain and a pharmacological approach employing administration of recombinant TPP1. While we clearly observed the expected AD phenotype of the J20 mice based on pathology and measurement of behavioral and cognitive defects, we found that elevation of TPP1 activity by either experimental approach failed to have any measurable beneficial effect on disease phenotype.

Mouse Models of Alzheimer's Disease.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes, eventually leading to dementia. The pathological hallmarks of AD are senile plaques and neurofibrillary tangles, which comprise abnormally aggregated β-amyloid peptide (Aβ) and hyperphosphorylated tau protein. To develop preventive, diagnostic, and therapeutic strategies for AD, it is essential to establish animal models that recapitulate the pathophysiological process of AD. In this review, we will summarize the advantages and limitations of various mouse models of AD, including transgenic, knock-in, and injection models based on Aβ and tau. We will also discuss other mouse models based on neuroinflammation because recent genetic studies have suggested that microglia are crucial in the pathogenesis of AD. Although each mouse model has its advantages and disadvantages, further research on AD pathobiology will lead to the establishment of more accurate mouse models, and accelerate the development of innovative therapeutics.

The Alzheimer's disease-associated gene TREML2 modulates inflammation by regulating microglia polarization and NLRP3 inflammasome activation.

Triggering receptor expressed on myeloid cells-like 2 (TREML2) is a newly identified susceptibility gene for Alzheimer's disease (AD). It encodes a microglial inflammation-associated receptor. To date, the potential role of microglial TREML2 in neuroinflammation in the context of AD remains unclear. In this study, APP/PS1 mice were used to investigate the dynamic changes of TREML2 levels in brain during AD progression. In addition, lipopolysaccharide (LPS) stimulation of primary microglia as well as a lentivirus-mediated TREML2 overexpression and knockdown were employed to explore the role of TREML2 in neuroinflammation in the context of AD. Our results show that TREML2 levels gradually increased in the brains of APP/PS1 mice during disease progression. LPS stimulation of primary microglia led to the release of inflammatory cytokines including interleukin-1β, interleukin-6, and tumor necrosis factor-α in the culture medium. The LPS-induced microglial release of inflammatory cytokines was enhanced by TREML2 overexpression and was attenuated by TREML2 knockdown. LPS increased the levels of microglial M1-type polarization marker inducible nitric oxide synthase. This effect was enhanced by TREML2 overexpression and ameliorated by TREML2 knockdown. Furthermore, the levels of microglial M2-type polarization markers CD206 and ARG1 in the primary microglia were reduced by TREML2 overexpression and elevated by TREML2 knockdown. LPS stimulation increased the levels of NLRP3 in primary microglia. The LPS-induced increase in NLRP3 was further elevated by TREML2 overexpression and alleviated by TREML2 knockdown. In summary, this study provides the first evidence that TREML2 modulates inflammation by regulating microglial polarization and NLRP3 inflammasome activation. These findings reveal the mechanisms by which TREML2 regulates microglial inflammation and suggest that TREML2 inhibition may represent a novel therapeutic strategy for AD.

Aptamer-Induced-Dimerization Strategy Attenuates AβO Toxicity through Modulating the Trophic Activity of PrPC Signaling

Current therapeutic strategies for Alzheimer's disease (AD) mainly focus on amyloid β oligomer (AβO) formation or clearance. However, most of them have failed to yield good clinical results. There is an urgent need to explore an alternative therapeutic target for AD treatments. Recent studies have indicated that the cellular prion protein (PrPC) is one of the cell-surface receptors of AβO that mediates related neurotoxicity. Besides, as a neuroprotective protein, the dimerization of PrPC seems to be critical for its trophic activity. We presume that modulating PrPC receptor activity could be another potential approach to abrogate AβO toxicity. In the present work, using an aptamer-induced dimerization (AID) strategy, we enforce PrPC dimerization and modulate its neurotrophic signaling. The AID strategy can attenuate AβO toxic action by (i) interfering with AβO-PrPC interaction and promoting neuroprotective shedding of PrPC; (ii) preventing the AβO-induced mitochondrial dysfunction and the caspase-3-induced apoptosis; and (iii) reducing the secretion of inflammatory cytokines and relieving the neuroinflammation microenvironment. Our findings suggest that the strategy targeting PrPC signaling may shed light on validating new therapeutic strategies in AD.