Aβ Clearance Research Articles

A Computational Approach in the Systematic Search of the Interaction Partners of Alternatively Spliced TREM2 Isoforms.

Alzheimer's disease is the most common form of dementia, characterized by the pathological accumulation of amyloid-beta (Aβ) plaques and tau neurofibrillary tangles. Triggering receptor expressed on myeloid cells 2 (TREM2) is increasingly recognized as playing a central role in Aβ clearance and microglia activation in AD. The TREM2 gene transcriptional product is alternatively spliced to produce three different protein isoforms. The canonical TREM2 isoform binds to DAP12 to activate downstream pathways. However, little is known about the function or interaction partners of the alternative TREM2 isoforms. The present study utilized a computational approach in a systematic search for new interaction partners of the TREM2 isoforms by integrating several state-of-the-art structural bioinformatics tools from initial large-scale screening to one-on-one corroborative modeling and eventual all-atom visualization. CD9, a cell surface glycoprotein involved in cell-cell adhesion and migration, was identified as a new interaction partner for two TREM2 isoforms, and CALM, a calcium-binding protein involved in calcium signaling, was identified as an interaction partner for a third TREM2 isoform, highlighting the potential role of cell adhesion and calcium regulation in AD.

Filicinic acid based meroterpenoids from Hypericum elodeoides and their anti-Alzheimer’s disease effects

(±)-Elodeoidileons A-L (1–12), 12 pairs of previously undescribed filicinic acid based meroterpenoids were isolated from Hypericum elodeoides with unique linear or angular 6/6/6 ring core. Modern spectroscopic techniques, modified Mosher’s method and quantum chemical calculations were used to identify the planner structures and configurations of 1–12. Additionally, the potential biosynthetic pathways for 1–12 were anticipated. Moreover, biological activity assessments suggested that 1a, 5a, and 11b could activate Retinoid X receptor-α (RXRα) transcription and enhance the ATP-binding cassette transporter A1 (ABCA1) protein’s expression. Fluorescence titration assay suggested that 1a might have a direct interaction with the RXRα-LBD protein, with an estimated Kd value of 5.85 μM. Moreover, molecular docking study confirmed the binding of 1a to RXRα and further validated by cellular thermal shift assay (CETSA). Thus, compound 1a may promote β-amyloid (Aβ) clearance by targeting RXRα and upregulating the expression of the ABCA1 protein, showing promise as anti-Alzheimer’s agent.

C-Reactive Protein, the Gliovascular Unit, and Alzheimer's Disease.

Alzheimer's disease (AD) pathogenesis is conditioned by the presence of amyloid beta (Aβ) and neuroinflammation. The gliovascular unit (GVU) illustrates the relationship between the vascular components of the brain and glial cells, particularly astrocytes, which are seen as critical elements mainly affected in this disease. In AD patients, the impairment of the GVU is seen as blood-brain barrier breakdown, decreased clearance of Aβ, and chronic inflammatory status. C-reactive protein (CRP) and its monomeric form (mCRP) are associated with endothelial dysfunction and amyloid plaque instability, contributing to neuroinflammation and neurodegeneration. The interconnections between the GVU and the dissociated form of CRP were demonstrated by mCRP implication in vascular permeability that supports inflammation and extravasation of pro-inflammatory cytokines into the brain parenchyma. Astrocytic activation and endfeet function alterations can exacerbate the progression of AD by elevating pro-inflammatory agents and vascular amyloid accumulations. This review aims to emphasize the synergistic link between the GVU and monomers of CRP in the perpetuation of the inflammatory status, exacerbating neurodegeneration and neuroinflammation. Understanding their implication in AD can bring insights into novel therapeutic strategies to reduce AD progression.

Tetrameric Transthyretin as a Protective Factor Against Alzheimer's Disease.

Transthyretin (TTR) is a tetrameric protein traditionally recognized for its role in transporting thyroxine and retinol. Recent research has highlighted the potential neuroprotective functions of TTR in the setting of Alzheimer's disease (AD), which is the most common form of dementia and is caused by the deposition of amyloid beta (Aβ) and the resulting cytotoxic effects. This paper explores the mechanisms of TTR protective action, including its interaction with Aβ to prevent fibril formation and promote Aβ clearance from the brain. It also synthesizes experimental evidence suggesting that enhanced TTR stability may mitigate neurodegeneration and cognitive decline in AD. Potential therapeutic strategies such as small molecule stabilizers of TTR are discussed, highlighting their role in enhancing TTR binding to Aβ and facilitating its clearance. By consolidating current knowledge and proposing directions for future research, this review aims to underscore the significance of TTR as a neuroprotective factor in AD and the potential implications for future research.

Switch to phagocytic microglia by CSFR1 inhibition drives amyloid-beta clearance from glutamatergic terminals rescuing LTP in acute hippocampal slices

Microglia, traditionally regarded as innate immune cells in the brain, drive neuroinflammation and synaptic dysfunctions in the early phases of Alzheimer disease (AD), acting upstream to Aβ accumulation. Colony stimulating factor 1-receptor (CSF-1R) is predominantly expressed on microglia and its levels are significantly increased in neurodegenerative diseases, possibly contributing to the chronic inflammatory microglial response. On the other hand, CSF-1R inhibitors confer neuroprotection in preclinical models of neurodegenerative diseases. Here, we determined the effects of the CSF-1R inhibitor PLX3397 on the Aβ-mediated synaptic alterations in ex vivo hippocampal slices. Electrophysiological findings show that PLX3397 rescues LTP impairment and neurotransmission changes induced by Aβ. In addition, using confocal imaging experiments, we demonstrate that PLX3397 stimulates a microglial transition toward a phagocytic phenotype, which in turn promotes the clearance of Aβ from glutamatergic terminals. We believe that the selective pruning of Aβ-loaded synaptic terminals might contribute to the restoration of LTP and excitatory transmission alterations observed upon acute PLX3397 treatment. This result is in accordance with the mechanism proposed for CSF1R inhibitors, that is to eliminate responsive microglia and replace it with newly generated, homeostatic microglia, capable of promoting brain repair. Overall, our findings identify a connection between the rapid microglia adjustments and the early synaptic alterations observed in AD, possibly highlighting a novel disease-modifying target.

Enhanced Brain Clearance of Tau and Amyloid-β in Alzheimer's Disease Patients by Transcranial Radiofrequency Wave Treatment: A Central Role of Vascular Endothelial Growth Factor (VEGF).

While drainage/removal of fluid and toxins from the brain by cerebrospinal fluid (CSF) directly into venous blood is well-known, a second drainage route has recently been (re)discovered-meningeal lymphatic vessels (mLVs)-which are responsible for up to half of total brain fluid/toxin drainage. The cytokine vascular endothelial growth factor (VEGF) increases mLV diameter and numbers to increase mLV drainage, resulting in increased mLV drainage. Alzheimer's disease (AD) is characterized by low plasma and CSF levels of VEGF. To determine if non-invasive transcranial radiofrequency wave treatment (TRFT), through modulation of VEGF levels in blood and CSF, can affect removal of toxins tau and amyloid-β (Aβ) from the brain. Eight mild/moderate AD subjects were given twice-daily 1-hour TRFT sessions at home by their caregivers. Blood and CSF samples were taken at baseline and following completion of 2 months of TRFT. In plasma and/or CSF, strong baseline correlations between VEGF levels and AD markers (t-tau, p-tau, Aβ1-40, Aβ1-42) were eliminated by TRFT. This effect was primarily due to TRFT-induced increases in VEGF levels in AD subjects with low or unmeasurable "baseline" VEGF levels. These increased VEGF levels were associated with increased clearance/drainage of tau and Aβ from the brain, likely through VEGF's actions on mLVs. A new mechanism of TRFT is identified (facilitation of brain tau and Aβ clearance via VEGF) that is likely contributory to TRFT's reversal of cognitive impairment in AD subjects. TRFT may be particularly effective for cognitive benefit in AD subjects who have low VEGF levels.

Explainable artificial intelligence identifies an AQP4 polymorphism-based risk score associated with brain amyloid burden

Aquaporin-4 (AQP4) is hypothesized to be a component of the glymphatic system, a pathway for removing brain interstitial solutes like amyloid-β (Aβ). Evidence exists that genetic variation of AQP4 impacts Aβ clearance, clinical outcome in Alzheimer’s disease as well as sleep measures. We examined whether a risk score calculated from several AQP4 single-nucleotide polymorphisms (SNPs) is related to Aβ neuropathology in older cognitively unimpaired white individuals. We used a machine learning approach and explainable artificial intelligence to extract information on synergistic effects of AQP4 SNPs on brain amyloid burden from the ADNI cohort. From this information, we formulated a sex-specific AQP4 SNP-based risk score and evaluated it using data from the screening process of the A4 study. We found in both cohorts significant associations of the risk score with brain amyloid burden. The results support the hypothesis of an involvement of the glymphatic system, and particularly AQP4, in brain amyloid aggregation pathology. They suggest also that different AQP4 SNPs exert a synergistic effect on the build-up of brain amyloid burden.

Assessing blood-brain barrier dysfunction and its association with Alzheimer’s pathology, cognitive impairment and neuroinflammation

BackgroundBlood-brain barrier (BBB) alterations may contribute to AD pathology through various mechanisms, including impaired amyloid-β (Aβ) clearance and neuroinflammation. Soluble platelet-derived growth factor receptor beta (sPDGFRβ) has emerged as a potential biomarker for BBB integrity. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) offers a direct assessment of BBB permeability. However, the relationship between BBB dysfunction, cognitive impairment, and AD pathology remains unclear, with inconsistent findings in the literature.MethodsWe conducted a cross-sectional study using data from the DELCODE and DESCRIBE cohorts to investigate BBB dysfunction in participants with normal cognition (NC), mild cognitive impairment (MCI), and AD dementia. BBB function was assessed using DCE-MRI and sPDGFRβ levels in cerebrospinal fluid and AD biomarkers Aβ and tau were measured. In a subset of patients, the CSF/plasma-ratio of albumin (QAlb) as a standard marker of BBB integrity and markers of neuroinflammation were analyzed.Results91 participants (NC: 44, MCI: 21, AD: 26) were included in the analysis. The average age was 74.4 years, 42% were female. Increased hippocampal BBB disruption was observed in the AD-group (Ktrans: 0.55 × 10− 3 min− 1 ± 0.74 × 10− 3 min− 1) but not the MCI-group (Ktrans: 0.177 × 10− 3 min− 1 ± 0.22 × 10− 3 min− 1), compared to the NC group (Ktrans: 0.19 × 10− 3 min− 1 ± 0.37 × 10− 3 min− 1, p < .01). sPDGFRβ was not significantly different between the cognitive groups. However, sPDGFRβ levels were significantly associated with age (r = .33, p < .01), independent of vascular risk factors. Further, sPDGFRβ showed significant positive associations with soluble Aβ levels (Aβ40: r = .57, p < .01; Aβ42: r = .39, p < .01) and YKL-40 (r = .53, p < .01), a marker of neuroinflammation. sPDGFRβ/DCE-MRI was not associated with overall AD biomarker positivity or APOE-status.ConclusionIn dementia, but not MCI, hippocampal BBB disruption was observed. sPDGFRβ increased with age and was associated with neuroinflammation independent of cognitive impairment. The association between Aβ and sPDGFRβ may indicate a bidirectional relationship reflecting pericytes’ clearance of soluble Aβ and/or vasculotoxic properties of Aβ.

Bifurcations in coupled amyloid-β aggregation-inflammation systems

A complex interplay between various processes underlies the neuropathology of Alzheimer’s disease (AD) and its progressive course. Several lines of evidence point to the coupling between Aβ aggregation and neuroinflammation and its role in maintaining brain homeostasis during the long prodromal phase of AD. Little is however known about how this protective mechanism fails and as a result, an irreversible and progressive transition to clinical AD occurs. Here, we introduce a minimal model of a coupled system of Aβ aggregation and inflammation, numerically simulate its dynamical behavior, and analyze its bifurcation properties. The introduced model represents the following events: generation of Aβ monomers, aggregation of Aβ monomers into oligomers and fibrils, induction of inflammation by Aβ aggregates, and clearance of various Aβ species. Crucially, the rates of Aβ generation and clearance are modulated by inflammation level following a Hill-type response function. Despite its relative simplicity, the model exhibits enormously rich dynamics ranging from overdamped kinetics to sustained oscillations. We then specify the region of inflammation- and coupling-related parameters space where a transition to oscillatory dynamics occurs and demonstrate how changes in Aβ aggregation parameters could shift this oscillatory region in parameter space. Our results reveal the propensity of coupled Aβ aggregation-inflammation systems to oscillatory dynamics and propose prolonged sustained oscillations and their consequent immune system exhaustion as a potential mechanism underlying the transition to a more progressive phase of amyloid pathology in AD. The implications of our results in regard to early diagnosis of AD and anti-AD drug development are discussed.

Tetramethylpyrazine Nitrone (TBN) Reduces Amyloid β Deposition in Alzheimer's Disease Models by Modulating APP Expression, BACE1 Activity, and Autophagy Pathways.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with age. A wealth of evidence indicates that the amyloid β (Aβ) aggregates result from dyshomeostasis between Aβ production and clearance, which plays a pivotal role in the pathogenesis of AD. Consequently, therapies targeting Aβ reduction represent a promising strategy for AD intervention. Tetramethylpyrazine nitrone (TBN) is a novel tetramethylpyrazine derivative with potential for the treatment of AD. Previously, we demonstrated that TBN markedly enhanced cognitive functions and decreased the levels of Aβ, APP, BACE 1, and hyperphosphorylated tau in 3×Tg-AD mice. However, the mechanism by which TBN inhibits Aβ deposition is still unclear. In this study, we employed APP/PS1 mice treated with TBN (60 mg/kg, ig, bid) for six months, and N2a/APP695swe cells treated with TBN (300 μM) to explore the mechanism of TBN in Aβ reduction. Our results indicate that TBN significantly alleviated cognitive impairment and reduced Aβ deposition in APP/PS1 mice. Further investigation of the underlying mechanisms revealed that TBN decreased the expression of APP and BACE1, activated the AMPK/mTOR/ULK1 autophagy pathway, inhibited the PI3K/AKT/mTOR/ULK1 autophagy pathway, and decreased the phosphorylation levels of JNK and ERK in APP/PS1 mice. Moreover, TBN was found to significantly reduce the mRNA levels of APP and BACE1, as well as those of SP1, CTCF, TGF-β, and NF-κB, transcription factors involved in regulating gene expression. Additionally, TBN was observed to decrease the level of miR-346 and increase the levels of miR-147 and miR-106a in the N2a/APP695swe cells. These findings indicate that TBN may reduce Aβ levels likely by reducing APP expression by regulating APP gene transcriptional factors and miRNAs, reducing BACE1 expression, and promoting autophagy activities.

The presence of circulating human apolipoprotein J reduces the occurrence of cerebral microbleeds in a transgenic mouse model with cerebral amyloid angiopathy

BackgroundCerebral amyloid angiopathy (CAA) is characterized by amyloid-β (Aβ) deposition in cerebral vessels, leading to lobar cerebral microbleeds (CMB) and intracerebral hemorrhages (ICH). Apolipoprotein J (ApoJ) is a multifunctional chaperone related to Aβ aggregation and clearance. Our study investigated the vascular impact of chronic recombinant human Apolipoprotein J (rhApoJ) treatment in a transgenic mouse model of β-amyloidosis with prominent CAA.MethodsTwenty-month-old APP23 C57BL/6 mice received 25 doses of rhApoJ (1 mg/kg) (n = 9) or saline (n = 8) intraperitoneally for 13 weeks, while Wild-type (WT) mice received saline (n = 13). Postmortem brains underwent T2*-weighted magnetic resonance imaging (MRI) to detect hemorrhagic lesions. Aβ levels and distribution, cerebral fibrinogen leakage, brain smooth muscle actin (sma), and plasma matrix metalloproteinases and inflammatory markers were analyzed after treatments. Additionally, plasma samples from 22 patients with lobar ICH were examined to determine the clinical relevance of the preclinical findings.ResultsrhApoJ-treated APP23 presented fewer cortical CMBs (50–300 μm diameter) (p = 0.012) and cortical larger hemorrhages (> 300 μm) (p = 0.002) than saline-treated mice, independently of Aβ brain levels. MRI-detected hemorrhagic lesions correlated with fibrinogen cerebral extravasation (p = 0.011). Additionally, rhApoJ-treated mice presented higher number of sma-positive vessels than saline-treated mice (p = 0.038). In rhApoJ-treated mice, human ApoJ was detected in plasma and in occasional leptomeningeal vessels, but not in the parenchyma, suggesting that its mechanism of action operates through the periphery. The administration of rhApoJ induced an increase in plasma Groα (p = 0.035) and MIP-1α (p = 0.035) levels, while lower MMP-12 (p = 0.046) levels, compared to the saline-treated group. In acute lobar ICH patients, MMP-12 plasma levels correlated with larger hemorrhage volume (p = 0.040) and irregular ICH shape (p = 0.036).ConclusionsChronic rhApoJ treatment in aged APP23 mice ameliorated CAA-related neurovascular damage by reducing the occurrence of CMB. We propose that rhApoJ may prevent blood-brain barrier (BBB) leakage and CMB appearance partly through circulating MMP-12 modulation.

Astrocytic autophagy plasticity modulates Aβ clearance and cognitive function in Alzheimer’s disease

BackgroundAstrocytes, one of the most resilient cells in the brain, transform into reactive astrocytes in response to toxic proteins such as amyloid beta (Aβ) in Alzheimer’s disease (AD). However, reactive astrocyte-mediated non-cell autonomous neuropathological mechanism is not fully understood yet. We aimed our study to find out whether Aβ-induced proteotoxic stress affects the expression of autophagy genes and the modulation of autophagic flux in astrocytes, and if yes, how Aβ-induced autophagy-associated genes are involved Aβ clearance in astrocytes of animal model of AD.MethodsWhole RNA sequencing (RNA-seq) was performed to detect gene expression patterns in Aβ-treated human astrocytes in a time-dependent manner. To verify the role of astrocytic autophagy in an AD mouse model, we developed AAVs expressing shRNAs for MAP1LC3B/LC3B (LC3B) and Sequestosome1 (SQSTM1) based on AAV-R-CREon vector, which is a Cre recombinase-dependent gene-silencing system. Also, the effect of astrocyte-specific overexpression of LC3B on the neuropathology in AD (APP/PS1) mice was determined. Neuropathological alterations of AD mice with astrocytic autophagy dysfunction were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through novel object recognition test (NOR) and novel object place recognition test (NOPR).ResultsHere, we show that astrocytes, unlike neurons, undergo plastic changes in autophagic processes to remove Aβ. Aβ transiently induces expression of LC3B gene and turns on a prolonged transcription of SQSTM1 gene. The Aβ-induced astrocytic autophagy accelerates urea cycle and putrescine degradation pathway. Pharmacological inhibition of autophagy exacerbates mitochondrial dysfunction and oxidative stress in astrocytes. Astrocyte-specific knockdown of LC3B and SQSTM1 significantly increases Aβ plaque formation and GFAP-positive astrocytes in APP/PS1 mice, along with a significant reduction of neuronal marker and cognitive function. In contrast, astrocyte-specific overexpression of LC3B reduced Aβ aggregates in the brain of APP/PS1 mice. An increase of LC3B and SQSTM1 protein is found in astrocytes of the hippocampus in AD patients.ConclusionsTaken together, our data indicates that Aβ-induced astrocytic autophagic plasticity is an important cellular event to modulate Aβ clearance and maintain cognitive function in AD mice.

Low-Density Lipoprotein Receptor-Related Protein 1 as a Potential Therapeutic Target in Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease impacting the lives of millions of people worldwide. The formation of amyloid β (Aβ) plagues in the brain is the main pathological hallmark of AD. The Aβ deposits are formed due to the imbalance between the production and Aβ clearance in the brain and across the blood-brain barrier (BBB). In this respect, low-density lipoprotein receptor-related protein 1 (LRP1) plays a significant role by mediating both brain Aβ production and clearance. Due to its important role in AD pathogenesis, LRP1 is considered an attractive drug target for AD therapies. In the present review, we summarize the current knowledge about the role of LRP1 in AD pathogenesis as well as recent findings on changes in LRP1 expression and function in AD. Finally, we discuss the advances in utilizing LRP1 as a drug target for AD treatments as well as future perspectives on LRP1 research.

Approaches for Increasing Cerebral Efflux of Amyloid-β in Experimental Systems.

Amyloid protein-β (Aβ) concentrations are increased in the brain in both early onset and late onset Alzheimer's disease (AD). In early onset AD, cerebral Aβ production is increased and its clearance is decreased, while increased Aβ burden in late onset AD is due to impaired clearance. Aβ has been the focus of AD therapeutics since development of the amyloid hypothesis, but efforts to slow AD progression by lowering brain Aβ failed until phase 3 trials with the monoclonal antibodies lecanemab and donanemab. In addition to promoting phagocytic clearance of Aβ, antibodies lower cerebral Aβ by efflux of Aβ-antibody complexes across the capillary endothelia, dissolving Aβ aggregates, and a "peripheral sink" mechanism. Although the blood-brain barrier is the main route by which soluble Aβ leaves the brain (facilitated by low-density lipoprotein receptor-related protein-1 and ATP-binding cassette sub-family B member 1), Aβ can also be removed via the blood-cerebrospinal fluid barrier, glymphatic drainage, and intramural periarterial drainage. This review discusses experimental approaches to increase cerebral Aβ efflux via these mechanisms, clinical applications of these approaches, and findings in clinical trials with these approaches in patients with AD or mild cognitive impairment. Based on negative findings in clinical trials with previous approaches targeting monomeric Aβ, increasing the cerebral efflux of soluble Aβ is unlikely to slow AD progression if used as monotherapy. But if used as an adjunct to treatment with lecanemab or donanemab, this approach might allow greater slowing of AD progression than treatment with either antibody alone.

Single-Cell RNA Sequencing Reveals Immunomodulatory Effects of Stem Cell Factor and Granulocyte Colony-Stimulating Factor Treatment in the Brains of Aged APP/PS1 Mice.

Alzheimer's disease (AD) leads to progressive neurodegeneration and dementia. AD primarily affects older adults with neuropathological changes including amyloid-beta (Aβ) deposition, neuroinflammation, and neurodegeneration. We have previously demonstrated that systemic treatment with combined stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) (SCF+G-CSF) reduces the Aβ load, increases Aβ uptake by activated microglia and macrophages, reduces neuroinflammation, and restores dendrites and synapses in the brains of aged APPswe/PS1dE9 (APP/PS1) mice. However, the mechanisms underlying SCF+G-CSF-enhanced brain repair in aged APP/PS1 mice remain unclear. This study used a transcriptomic approach to identify the potential mechanisms by which SCF+G-CSF treatment modulates microglia and peripheral myeloid cells to mitigate AD pathology in the aged brain. After injections of SCF+G-CSF for 5 consecutive days, single-cell RNA sequencing was performed on CD11b+ cells isolated from the brains of 28-month-old APP/PS1 mice. The vast majority of cell clusters aligned with transcriptional profiles of microglia in various activation states. However, SCF+G-CSF treatment dramatically increased a cell population showing upregulation of marker genes related to peripheral myeloid cells. Flow cytometry data also revealed an SCF+G-CSF-induced increase of cerebral CD45high/CD11b+ active phagocytes. SCF+G-CSF treatment robustly increased the transcription of genes implicated in immune cell activation, including gene sets that regulate inflammatory processes and cell migration. The expression of S100a8 and S100a9 was robustly enhanced following SCF+G-CSF treatment in all CD11b+ cell clusters. Moreover, the topmost genes differentially expressed with SCF+G-CSF treatment were largely upregulated in S100a8/9-positive cells, suggesting a well-conserved transcriptional profile related to SCF+G-CSF treatment in resident and peripherally derived CD11b+ immune cells. This S100a8/9-associated transcriptional profile contained notable genes related to pro-inflammatory and anti-inflammatory responses, neuroprotection, and Aβ plaque inhibition or clearance. Altogether, this study reveals the immunomodulatory effects of SCF+G-CSF treatment in the aged brain with AD pathology, which will guide future studies to further uncover the therapeutic mechanisms.

Microglia Gravitate toward Amyloid Plaques Surrounded by Externalized Phosphatidylserine via TREM2.

Microglia play a crucial role in synaptic elimination by engulfing dystrophic neurons via triggering receptors expressed on myeloid cells 2 (TREM2). They are also involved in the clearance of beta-amyloid (Aβ) plaques in Alzheimer's disease (AD); nonetheless, the driving force behind TREM2-mediated phagocytosis of beta-amyloid (Aβ) plaques remains unknown. Here, using advanced 2D/3D/4D co-culture systems with loss-of-function mutations in TREM2 (a frameshift mutation engineered in exon 2) brain organoids/microglia/assembloids, it is identified that the clearance of Aβ via TREM2 is accelerated by externalized phosphatidylserine (ePtdSer) generated from dystrophic neurons surrounding the Aβ plaques. Moreover, it is investigated whether microglia from both sporadic (CRISPR-Cas9-based APOE4 lines) and familial (APPNL-G-F/MAPT double knock-in mice) AD models show reduced levels of TREM2 and lack of phagocytic activity toward ePtdSer-positive Aβ plaques. Herein new insight is provided into TREM2-dependent microglial phagocytosis of Aβ plaques in the context of the presence of ePtdSer during AD progression.

1-Deoxynojirimycin attenuates pathological markers of Alzheimer's disease in the invitro model of neuronal insulin resistance.

Insulin resistance, the hallmark of type 2 diabetes mellitus (T2DM), has emerged as a pathological feature in Alzheimer's disease (AD). Given the shared role of insulin resistance in T2DM and AD, repurposing peripheral insulin sensitizers is a promising strategy to preserve neuronal insulin sensitivity and prevent AD. 1-Deoxynojirimycin (DNJ), a bioactive iminosugar, exhibited insulin-sensitizing effects in metabolic tissues and was detected in brain tissue post-oral intake. However, its impact on brain and neuronal insulin signaling has not been described. Here, we investigated the effect of DNJ treatment on insulin signaling and AD markers in insulin-resistant human SK-N-SH neuroblastoma, a cellular model of neuronal insulin resistance. Our findings show that DNJ increased the expression of insulin signaling genes and the phosphorylation status of key molecules implicated in insulin resistance (Y1146-pIRβ, S473-pAKT, S9-GSK3B) while also elevating the expression of glucose transporters Glut3 and Glut4, resulting in higher glucose uptake upon insulin stimuli. DNJ appeared to mitigate the insulin resistance-driven increase in phosphorylated tau and Aβ1-42 levels by promoting insulin-induced phosphorylation of GSK3B (a major tau kinase) and enhancing mRNA expression of the insulin-degrading enzyme (IDE) pivotal for insulin and Aβ clearance. Overall, our study unveils probable mechanisms underlying the potential benefits of DNJ for AD, wherein DNJ attenuates tau and amyloid pathologies by reversing neuronal insulin resistance. This provides a scientific basis for expanding the use of DNJ-containing products for neuroprotective purposes and prompts further research into compounds with similar mechanisms of action.

Genetic biomarkers of cognitive impairment and dementia of potential interest in CKD patients.

This review discusses genetic variants associated with cognitive dysfunction in chronic kidney disease (CKD) patients, emphasising the limited research in this area. Four studies have explored genetic markers of cognitive dysfunction in CKD, with findings suggesting shared genetic biomarkers between Alzheimer's Disease and CKD.Because of the limited specific research on genetic markers of cognitive dysfunction and dementia in CKD, we extracted data from the current literature studies on genetic markers in the general population that may be relevant to the CKD population. These markers include Apolipoprotein E (APOE), Complement Receptor 1 (CR1), Clusterin (CLU), Sortilin-related receptor 1 (SORL1), Catechol-O-methyltransferase (COMT), and Brain-derived neurotrophic factor (BDNF), all of which are known to be associated with cognitive dysfunction and dementia in other populations. These genes play various roles in lipid metabolism, inflammation, Aβ clearance, and neuronal function, making them potential candidates for studying cognitive decline in CKD patients.CKD-specific research is needed to understand the role of these genetic markers in CKD-related cognitive dysfunction. Investigating how these genes influence cognitive decline in CKD patients could provide valuable insights into early detection, targeted interventions, and personalised treatment strategies. Overall, genetic studies to enhance our understanding and management of cognitive dysfunction in CKD represent a clinical research priority in this population.

Long-Term High-Fat Diet Impairs AQP4-Mediated Glymphatic Clearance of Amyloid Beta.

As a risk factor for Alzheimer's disease (AD), studies have demonstrated that long-term high-fat diet (HFD) could accelerate the deposition of amyloid beta (Aβ) in the brain. The glymphatic system plays a critical role in Aβ clearance from the brain. However, studies investigating the effects of long-term HFD on glymphatic function have reported paradoxical outcomes, and whether glymphatic dysfunction is involved in the disturbance of Aβ clearance in long-term HFD-fed mice has not been determined. In the present study, we injected fluorescently labeled Aβ into the hippocampus and found that Aβ clearance was decreased in HFD-fed mice. We found that long-term HFD-fed mice had decreased glymphatic function by injecting fluorescent tracers into the cisterna magna and corpus striatum. In long-term HFD-fed mice, aquaporin-4 (AQP4) polarization in the cortex was disrupted, and glymphatic clearance activity was positively correlated with the AQP4 polarization index. In HFD-fed mice, the disturbance of Aβ clearance from the hippocampus was exacerbated by TGN-020, a specific inhibitor of AQP4, whereas TGN-073, an enhancer of AQP4, ameliorated it. These findings suggest that long-term HFD disrupts Aβ clearance by inhibiting AQP4-mediated glymphatic function. The underlying mechanism may involve the disruption of AQP4 polarization.

Inhibition of BACE1 affected both its Aβ producing and degrading activities and increased Aβ42 and Aβ40 levels at high-level BACE1 expression

The beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the predominant β-secretase, cleaving the amyloid precursor protein (APP) via the amyloidogenic pathway. In addition, BACE1 as an amyloid degrading enzyme (ADE), cleaves Aβ to produce the C-terminally truncated non-toxic Aβ fragment Aβ34 which is an indicator of amyloid clearance.Here, we analyzed effects of BACE1 inhibitors on its opposing enzymatic functions, i.e., amyloidogenic (Aβ producing) and amyloidolytic (Aβ degrading) activities, using cell culture models with varying BACE1/APP ratios. Under high level BACE1 expression, low-dose inhibition unexpectedly yielded a two-fold increase in Aβ42 and Aβ40 levels. The concomitant decrease in Aβ34 and secreted APPβ levels suggested that the elevated Aβ42 and Aβ40 levels were due to the attenuated Aβ degrading activity of BACE1. Notably, the amyloidolytic activity of BACE1 was impeded at lower BACE1 inhibitor concentrations compared to its amyloidogenic activity, thereby suggesting that the Aβ degrading activity of BACE1 was more sensitive to inhibition than its Aβ producing activity. Under endogenous BACE1 and APP levels, “low-dose” BACE1 inhibition affected both the Aβ producing and degrading activities of BACE1, i.e., significantly increased Aβ42/Aβ40 ratio and decreased Aβ34 levels, respectively. Further, we incubated recombinant BACE1 with synthetic Aβ peptides and found that BACE1 has higher affinity for Aβ substrates over APP. In summary, our results suggest that stimulating BACE1’s ADE activity and halting Aβ production without decreasing Aβ clearance could still be a promising therapeutic approach with new, yet to be developed, BACE1 modulators.