Therapeutic Strategy For Alzheimer's Disease Research Articles

Gene expression patterns of CRYM and SIGLEC10 in Alzheimer's disease: potential early diagnostic indicators.

Alzheimer's disease (AD) is a neurological condition that may lead to dementia as well as a slow and steady decline in cognitive ability. Finding early signs that may be used in the diagnosis of ADis still a difficult aim to achieve in the field of medical practice. The purpose of this research was to investigate to determineany differences in the gene expression patterns of crystallin mu (CRYM) and sialic acid-binding immunoglobulin-like lectin 10 (SIGLEC10) in whole blood samples obtained from fifty individuals who were diagnosed with ADand fifty individuals as a control group. When compared with controls, it was discovered that the expression of the CRYM gene was substantially decreased in AD patients, but the expression of the SIGLEC10 gene was significantly higher. A positive correlation between CRYM and SIGLEC10 was noticed solely in patients with AD. Furthermore, assessing the diagnostic value of these genes, CRYM and SIGLEC10 transcript levels displayed an area under the curve (AUC) of 0.74 and 0.81, respectively. These results suggest that alterations in CRYM and SIGLEC10 expression may be implicated in AD pathology and that these genes expression levels can potentially serve as biomarkers for early detection and diagnosis of AD. Nevertheless, further validation of these findings requires the inclusion of more extensive and heterogeneous cohorts. The findings derived from this study possess the capability to offer a significant contribution towards the progression of innovative diagnostic and therapeutic strategies for AD.

Modulation of Tau Pathology in Alzheimer's Disease by Dietary Bioactive Compounds.

Tau is a microtubule-associated protein essential for microtubule assembly and stability in neurons. The abnormal intracellular accumulation of tau aggregates is a major characteristic of brains from patients with Alzheimer's disease (AD) and other tauopathies. In AD, the presence of neurofibrillary tangles (NFTs), which is composed of hyperphosphorylated tau protein, is positively correlated with the severity of the cognitive decline. Evidence suggests that the accumulation and aggregation of tau cause synaptic dysfunction and neuronal degeneration. Thus, the prevention of abnormal tau phosphorylation and elimination of tau aggregates have been proposed as therapeutic strategies for AD. However, currently tau-targeting therapies for AD and other tauopathies are limited. A number of dietary bioactive compounds have been found to modulate the posttranslational modifications of tau, including phosphorylation, small ubiquitin-like modifier (SUMO) mediated modification (SUMOylation) and acetylation, as well as inhibit tau aggregation and/or promote tau degradation. The advantages of using these dietary components over synthetic substances in AD prevention and intervention are their safety and accessibility. This review summarizes the mechanisms leading to tau pathology in AD and highlights the effects of bioactive compounds on the hyperphosphorylation, aggregation and clearance of tau protein. The potential of using these bioactive compounds for AD prevention and intervention is also discussed.

Prevention of amyloid β fibril deposition on the synaptic membrane in the precuneus by ganglioside nanocluster-targeting inhibitors.

Alzheimer's disease (AD), a progressive neurodegenerative condition, is one of the most common causes of dementia. Senile plaques, a hallmark of AD, are formed by the accumulation of amyloid β protein (Aβ), which starts to aggregate before the onset of the disease. Gangliosides, sialic acid-containing glycosphingolipids, play a key role in the formation of toxic Aβ aggregates. In membrane rafts, ganglioside-bound complexes (GAβ) act as nuclei for Aβ assembly, suggesting that GAβ is a promising target for AD therapy. The formation of GAβ-induced Aβ assemblies has been evaluated using reconstituted planar lipid membranes composed of synaptosomal plasma membrane (SPM) lipids extracted from human and mouse brains. Although the effects of gangliosides on Aβ accumulation in the precuneus have been established, effects on Aβ fibrils have not been determined. In this study, Aβ42 fibrils on reconstituted membranes composed of SPM lipids prepared from the precuneus cortex of human autopsied brains were evaluated by atomic force microscopy. In particular, Aβ42 accumulation, as well as the fibril number and size were higher for membranes with precuneus lipids than for membranes with calcarine cortex lipids. In addition, artificial peptide inhibitors targeting Aβ-sensitive ganglioside nanoclusters cleared Aβ assemblies on synaptic membranes in the brain, providing a novel therapeutic strategy for AD.

Neuromodulation in Alzheimer’s Disease in the Therapy Process

Increasing prevalence in the near future of Alzheimer’s disease (AD) has been statistically predicted. As current pharmacological treatments turn out to be limited for the long-term clinical effects accompanying various side effects and complications, new schemes are in urgent need of a relatively safer and more effective treatment. In recent years, neuromodulation technologies such as optogenetics, transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), transcranial electrical stimulation (tES), deep brain stimulation (DBS), and focused ultrasound (FUS), which are proven with potential remedial effectiveness in several mental diseases, emerge to be a prospective therapeutic strategy for AD. By applying optical, magnetic, as well as electronic technology, modulations on specific brain regions can be achieved. And by applying ultrasonic technology, the process of medical molecules passing through the brain-blood barrier (BBB) can be facilitated. This article summarizes the current knowledge of some main neuromodulation technologies and provides insight into their possibilities for clinical application. By further illuminating the clinical effects, advantages, and limitations of these technologies, the article may help to guide clinical practice and enlighten new ideas for therapeutic strategy in AD.

Novel systemic delivery of a peptide‐mediated anti‐sense oligonucleotide to reduce α‐synuclein in a mouse model of Alzheimer’s Disease

AbstractBackgroundNeurodegenerative disorders of aging are characterized by the progressive accumulation of proteins such as α‐synuclein (α‐syn) and amyloid beta (Aβ). Misfolded and aggregated α‐syn has been implicated in neurological disorders such as Parkinson’s disease (PD), and Dementia with Lewy Bodies (DLB), but less so in Alzheimer’s Disease (AD). However, accumulation of α‐syn has been confirmed in over 50% of postmortem brains of AD patients. To date, no therapeutic strategy has consistently downregulated α‐syn in AD.MethodHere we tested the hypothesis that using a peptide (ApoB11) that binds a modified antisense oligonucleotide (2’‐O‐methyl si α‐syn or 2’‐OMe) for transport across the blood‐brain barrier following systemic administration, would downregulate α‐syn expression in an AD mouse model and improve behavioral and neuropathologic phenotypes. We tested the efficacy of the ASO in knocking down α‐syn both in vitro, using neuronal cell lines, and in vivo by measuring α‐syn levels in brains of treated mice with 2mg/kg at 6, 7 and 8 months of age.ResultWe found that treatment of APP transgenic mice with systemic delivery of ApoB11:ASO‐α‐syn reduces expression of α‐synuclein in specific regions of hippocampi of 9 month‐old APP transgenic mice. Downregulation of α‐syn led to a significant reduction of Aβ plaques burden, rescued neuronal loss and prevented astrogliosis, as compared to untreated PSAPP mice. Importantly, we found that AD mice treated with the ASO‐syn had greatly improved hippocampal and spatial memory function as shown by Morris Water Maze tests.ConclusionCollectively, the data shown in this work supports the use of ApoB11:ASO α‐syn conjugates delivered systemically to downregulate α‐syn as a promising future therapeutic strategy in AD. Our work suggests that knocking down α‐syn could be necessary to prevent neuropathology and prevent spatial memory loss.

PSEN2 poison exon inclusion is common across brain regions in late‐onset Alzheimer’s disease

AbstractBackgroundPathogenic variants in APP, PSEN1 and PSEN2 can cause early‐onset familial Alzheimer’s disease (AD). The molecular events leading to AD in individuals with late‐onset sporadic AD are still unclear even though they share the same clinical and pathological features of AD.MethodUsing targeted PacBio long read isoform sequencing (Iso‐Seq), we recently reported the characterization of tens of thousands of complete PSEN1 and PSEN2 transcripts in the prefrontal cortex of individuals with sporadic AD, familial AD (carrying PSEN1 and PSEN2 pathogenic variants), and controls.ResultWe found several alternative splicing differences in PSEN2 that are significantly elevated in sporadic AD including inclusion of a human‐specific cryptic exon present in intron 9 of PSEN2 (termed exon 9B) present in 11.8% of full‐length reads in sporadic AD samples relative to 1.9% of controls (p = 0.002) and 3.4% of PSEN variant carriers (p = 0.005) as well as a 77bp intron retention product prior to exon 6. These PSEN2 splice products are predicted to generate a prematurely truncated PSEN2 protein and were confirmed in an independent RNA‐seq dataset of ∼80 AD cases and ∼80 controls from cerebellum tissue (Course et al., Brain 2022). To extend these findings we analyzed PSEN2 exon 9B isoform levels in parietal and temporal lobe tissue samples. We found exon 9B was significantly elevated in sporadic AD relative to controls in the parietal lobe (p = 0.02) as well as the temporal lobe (p = <0.001). However, levels of exon 9B were independent of TDP‐43 pathology or MSUT2 protein levels, which is intriguing given their roles as RNA binding proteins implicated in AD. We are working to establish the consequence of exon 9B inclusion in APP processing, Aβ and PSEN2 protein products in addition to possible cell autonomous roles for PSEN2 splice variants in microglia by leveraging single cell sequencing data.ConclusionCollectively, our findings expand our understanding of PSEN2 splice variants in the development of late‐onset sporadic AD, which can point to novel therapeutic strategies for AD.

Establishment and application of a microglial phagocytosis/cell health high content assay for Alzheimer’s disease drug discovery targeting microglia

AbstractBackgroundTargeting microglial phagocytosis has been proposed as a therapeutic strategy for Alzheimer’s disease drug discovery. A reliable cellular assay capable of measuring drug‐regulated phagocytosis activity while simultaneously measuring treatment‐caused cell stress and toxicity is needed for drug discovery research targeting microglia. This need motivated us to develop and establish a high content microglial phagocytosis/cell health assay to meet the challenge.MethodThe assay uses 384‐well cellular imaging plates, microglial cell lines (HMC3 and BV2) and mouse primary microglia, pHrodo‐myelin/membrane debris as ligand, and a high content imaging system for imaging and analysis. Assay procedures include 1) plate cells on day 1 and incubate cell plates overnight in 37oC; 2) treat cells with compounds on day 2; 3) add pHrodo‐myelin/membrane debris to cell plates on day 3 and incubate in 37oC for 20 hours; 4) stain cell nuclei with Hoechst‐33342 for 30 min before performing high content imaging and analysis on day 4. Three selected parameters are measured from cell images: 1) mean total fluorescence intensity per cell of pHrodo‐myelin/membrane debris in phagocytosis vesicles to quantify phagocytosis; 2) cell counts per well (assessing effects on proliferation and cell death); and 3) average nuclear intensity (detecting induced apoptosis).ResultVarious treatments targeting different mechanisms regulating microglial phagocytosis were tested; we observed that Cytochalasin D inhibited phagocytosis, LPS stimulated phagocytosis in BV2 cells but not HMC3 cells, Idelalisib (PI3Kd inhibitor) inhibited HMC3 cell phagocytosis, and Saracatinib (Src/abl family of kinases inhibitor) stimulated HMC3 phagocytosis. These results validated the assay for use in drug discovery targeting microglial phagocytosis. With the assay, we identified some INPP5D inhibitors and some PLCG2 activators stimulated phagocytosis in a concentration range without significant cell stress/toxicity with all three cell types tested.ConclusionA microglial phagocytosis/cell health assay was established. The simultaneous measurement of phagocytosis and cell health allows for the distinction of drug effects on regulation of phagocytosis from cellular stress/toxicity‐related changes, a distinguishing feature of the assay, which helped compound selection of drug discovery projects targeting INPP5D and PLCG2 respectively.

Clusterin is a Potential Therapeutic Target in Alzheimer's Disease.

In recent years, Clusterin, a glycosylated protein with multiple biological functions, has attracted extensive research attention. It is closely associated with the physiological and pathological states within the organism. Particularly in Alzheimer's disease (AD) research, Clusterin plays a significant role in the disease's occurrence and progression. Numerous studies have demonstrated a close association between Clusterin and AD. Firstly, the expression level of Clusterin in the brain tissue of AD patients is closely related to pathological progression. Secondly, Clusterin is involved in the deposition and formation of β-amyloid, which is a crucial process in AD development. Furthermore, Clusterin may affect the pathogenesis of AD through mechanisms such as regulating inflammation, controlling cell apoptosis, and clearing pathological proteins. Therefore, further research on the relationship between Clusterin and AD will contribute to a deeper understanding of the etiology of this neurodegenerative disease and provide a theoretical basis for developing early diagnostic and therapeutic strategies for AD. This also makes Clusterin one of the research focuses as a potential biomarker for AD diagnosis and treatment monitoring.

N6-methyladenosine-modified circRIMS2 mediates synaptic and memory impairments by activating GluN2B ubiquitination in Alzheimer's disease

BackgroundSynaptic degeneration occurs in the early stage of Alzheimer's disease (AD) before devastating symptoms, strongly correlated with cognitive decline. Circular RNAs (circRNAs) are abundantly enriched in neural tissues, and aberrant expression of circRNAs precedes AD symptoms, significantly correlated with clinical dementia severity. However, the direct relationship between circRNA dysregulation and synaptic impairment in the early stage of AD remains poorly understood.MethodsHippocampal whole-transcriptome sequencing was performed to identify dysregulated circRNAs and miRNAs in 4-month-old wild-type and APP/PS1 mice. RNA antisense purification and mass spectrometry were utilized to unveil interactions between circRIMS2 and methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL3). The roles of circRIMS2/miR-3968 in synaptic targeting of UBE2K-mediated ubiquitination of GluN2B subunit of NMDA receptor were evaluated via numerous lentiviruses followed by morphological staining, co-immunoprecipitation and behavioral testing. Further, a membrane-permeable peptide was used to block the ubiquitination of K1082 on GluN2B in AD mice.ResultscircRIMS2 was significantly upregulated in 4-month-old APP/PS1 mice, which was mediated by METTL3-dependent N6-methyladenosine (m6A) modification. Overexpression of circRIMS2 led to synaptic and memory impairments in 4-month-old C57BL/6 mice. MiR-3968/UBE2K was validated as the downstream of circRIMS2. Elevated UBE2K induced synaptic dysfunction of AD through ubiquitinating K1082 on GluN2B. Silencing METTL3 or blocking the ubiquitination of K1082 on GluN2B with a short membrane-permeable peptide remarkably rescued synaptic dysfunction in AD mice.ConclusionsIn conclusion, our study demonstrated that m6A-modified circRIMS2 mediates the synaptic and memory impairments in AD by activating the UBE2K-dependent ubiquitination and degradation of GluN2B via sponging miR-3968, providing novel therapeutic strategies for AD.

Activation of neurogenesis in the hippocampus is a novel therapeutic target for Alzheimer's disease.

Highlights Targeting single mechanisms of physiological (aging) and pathological (neurodegeneration) loss of function in the brain may not be sufficient. Cell–cell interactions between transplanted adult stem cells and resident cells via gap junctions have the potential to support the aging or diseased brain. These cell–cell interactions can also increase hippocampal neurogenesis. This may be a novel therapeutic strategy for Alzheimer's disease and other neurodegenerative diseases that could be applied alongside any established treatments.

Effect of woohwangchungsimwon and donepezil co-treatment on cognitive function and serum metabolic profiles in a scopolamine-induced model of Alzheimer's disease

Ethnopharmacological relevanceWoohwangchungsimwon (WCW) is a traditional medicine used in East Asian countries to treat central nervous system disorders. Reported pharmacological properties include antioxidant effects, enhanced learning and memory, and protection against ischemic neuronal cell death, supporting its use in treating neurodegenerative diseases like Alzheimer's disease (AD). Aim of the studyThe study aims to assess the effects of co-treatment with WCW and donepezil on cognitive functions and serum metabolic profiles in a scopolamine-induced AD model. Materials and methodsCell viability and reactive oxygen species (ROS) levels were measured in amyloid β-peptide25–35 (Aβ25–35)-induced SH-SY5Y cells. An AD model was established in ICR mice by intraperitoneal scopolamine administration. Animals underwent the step-through passive avoidance test (PAT) and Morris water maze (MWM) test. Hippocampal tissues were collected to examine specific protein expression. Serum metabolic profiles were analyzed using nuclear magnetic resonance (NMR) spectroscopy. ResultsCo-treatment with WCW and donepezil increased cell viability and reduced ROS production in Aβ25–35-induced SH-SY5Y cells compared to that with donepezil treatment alone. Co-treatment improved cognitive functions and was comparable to donepezil treatment alone in the PAT and MWM tests. Pathways related to tyrosine, phenylalanine, and tryptophan biosynthesis, phenylalanine metabolism, and cysteine and methionine metabolism were altered by co-treatment. Levels of tyrosine and methionine, major serum metabolites in these pathways, were significantly reduced after co-treatment. ConclusionsCo-treatment with WCW and donepezil shows promise as a therapeutic strategy for AD and is comparable to donepezil alone in improving cognitive function. Reduced tyrosine and methionine levels after co-treatment may enhance cognitive function by mitigating hypertyrosinemia and hyperhomocysteinemia, known risk factors for AD. The serum metabolic profiles obtained in this study can serve as a foundation for developing other bioactive compounds using a scopolamine-induced mouse model.

Mechanistic Intimate Insights into the Role of Hydrogen Sulfide in Alzheimer's Disease: A Recent Systematic Review.

In the rapidly evolving field of Alzheimer's Disease (AD) research, the intricate role of Hydrogen Sulfide (H2S) has garnered critical attention for its diverse involvement in both pathological substrates and prospective therapeutic paradigms. While conventional pathophysiological models of AD have primarily emphasized the significance of amyloid-beta (Aβ) deposition and tau protein hyperphosphorylation, this targeted systematic review meticulously aggregates and rigorously appraises seminal contributions from the past year elucidating the complex mechanisms of H2S in AD pathogenesis. Current scholarly literature accentuates H2S's dual role, delineating its regulatory functions in critical cellular processes-such as neurotransmission, inflammation, and oxidative stress homeostasis-while concurrently highlighting its disruptive impact on quintessential AD biomarkers. Moreover, this review illuminates the nuanced mechanistic intimate interactions of H2S in cerebrovascular and cardiovascular pathology associated with AD, thereby exploring avant-garde therapeutic modalities, including sulfurous mineral water inhalations and mud therapy. By emphasizing the potential for therapeutic modulation of H2S via both donors and inhibitors, this review accentuates the imperative for future research endeavors to deepen our understanding, thereby potentially advancing novel diagnostic and therapeutic strategies in AD.

Proteasome inhibition protects blood–brain barrier P-glycoprotein and lowers Aβ brain levels in an Alzheimer’s disease model

BackgroundLoss of P-glycoprotein (P-gp) at the blood–brain barrier contributes to amyloid-β (Aβ) brain accumulation in Alzheimer’s disease (AD). Using transgenic human amyloid precursor protein (hAPP)-overexpressing mice (Tg2576), we previously showed that Aβ triggers P-gp loss by activating the ubiquitin–proteasome pathway, which leads to P-gp degradation. Furthermore, we showed that inhibiting the ubiquitin-activating enzyme (E1) prevents P-gp loss and lowers Aβ accumulation in the brain of hAPP mice. Based on these data, we hypothesized that repurposing the FDA-approved proteasome inhibitor, bortezomib (Velcade®; BTZ), protects blood–brain barrier P-gp from degradation in hAPP mice in vivo.MethodsWe treated hAPP mice with the proteasome inhibitor BTZ or a combination of BTZ with the P-gp inhibitor cyclosporin A (CSA) for 2 weeks. Vehicle-treated wild-type (WT) mice were used as a reference for normal P-gp protein expression and transport activity. In addition, we used the opioid receptor agonist loperamide as a P-gp substrate in tail flick assays to indirectly assess P-gp transport activity at the blood–brain barrier in vivo. We also determined P-gp protein expression by Western blotting, measured P-gp transport activity levels in isolated brain capillaries with live cell confocal imaging and assessed Aβ plasma and brain levels with ELISA.ResultsWe found that 2-week BTZ treatment of hAPP mice restored P-gp protein expression and transport activity in brain capillaries to levels found in WT mice. We also observed that hAPP mice displayed significant loperamide-induced central antinociception compared to WT mice indicating impaired P-gp transport activity at the blood–brain barrier of hAPP mice in vivo. Furthermore, BTZ treatment prevented loperamide-induced antinociception suggesting BTZ protected P-gp loss in hAPP mice. Further, BTZ-treated hAPP mice had lower Aβ40 and Aβ42 brain levels compared to vehicle-treated hAPP mice.ConclusionsOur data indicate that BTZ protects P-gp from proteasomal degradation in hAPP mice, which helps to reduce Aβ brain levels. Our data suggest that the proteasome system could be exploited for a novel therapeutic strategy in AD, particularly since increasing Aβ transport across the blood–brain barrier may prove an effective treatment for patients.

Neural stem cell-derived exosomes promote mitochondrial biogenesis and restore abnormal protein distribution in a mouse model of Alzheimer's disease.

Abstract JOURNAL/nrgr/04.03/01300535-202407000-00040/figure1/v/2023-11-20T171125Z/r/image-tiff Mitochondrial dysfunction is a hallmark of Alzheimer's disease. We previously showed that neural stem cell-derived extracellular vesicles improved mitochondrial function in the cortex of APP/PS1 mice. Because Alzheimer's disease affects the entire brain, further research is needed to elucidate alterations in mitochondrial metabolism in the brain as a whole. Here, we investigated the expression of several important mitochondrial biogenesis-related cytokines in multiple brain regions after treatment with neural stem cell-derived exosomes and used a combination of whole brain clearing, immunostaining, and lightsheet imaging to clarify their spatial distribution. Additionally, to clarify whether the sirtuin 1 (SIRT1)-related pathway plays a regulatory role in neural stem cell-derived exosomes interfering with mitochondrial functional changes, we generated a novel nervous system-SIRT1 conditional knockout APP/PS1 mouse model. Our findings demonstrate that neural stem cell-derived exosomes significantly increase SIRT1 levels, enhance the production of mitochondrial biogenesis-related factors, and inhibit astrocyte activation, but do not suppress amyloid-β production. Thus, neural stem cell-derived exosomes may be a useful therapeutic strategy for Alzheimer's disease that activates the SIRT1-PGC1α signaling pathway and increases NRF1 and COXIV synthesis to improve mitochondrial biogenesis. In addition, we showed that the spatial distribution of mitochondrial biogenesis-related factors is disrupted in Alzheimer's disease, and that neural stem cell-derived exosome treatment can reverse this effect, indicating that neural stem cell-derived exosomes promote mitochondrial biogenesis.

Methylene blue accelerates liquid-to-gel transition of tau condensates impacting tau function and pathology

Preventing tau aggregation is a potential therapeutic strategy in Alzheimer’s disease and other tauopathies. Recently, liquid–liquid phase separation has been found to facilitate the formation of pathogenic tau conformations and fibrillar aggregates, although many aspects of the conformational transitions of tau during the phase transition process remain unknown. Here, we demonstrate that the tau aggregation inhibitor methylene blue promotes tau liquid–liquid phase separation and accelerates the liquid-to-gel transition of tau droplets independent of the redox activity of methylene blue. We further show that methylene blue inhibits the conversion of tau droplets into fibrils and reduces the cytotoxicity of tau aggregates. Although gelation slows down the mobility of tau and tubulin, it does not impair microtubule assembly within tau droplets. These findings suggest that methylene blue inhibits tau amyloid fibrillization and accelerates tau droplet gelation via distinct mechanisms, thus providing insights into the activity of tau aggregation inhibitors in the context of phase transition.

Self-Destructive Nanoscavengers Capture and Clear Neurotoxic Soluble β-Amyloid Aggregates.

Cerebral soluble β-amyloid aggregates (sAβs) accumulation is one of the most important causes in Alzheimer's disease (AD) progression. In order to mitigate the neurotoxicity induced by sAβs and achieve enhanced AD therapeutic outcomes, robust sAβs clearance become an emerging task. Herein, a self-destructive nanoscavenger (SDNS) is reported based on multifunctional peptide-polymer complexes that can capture extracellular sAβs via hydrogen-bonding interactions and deliver them into microglial lysosomes. The internalized SDNS then occurs self-destruction within lysosomes and upregulates autophagy, thereby promoting the degradation of neurotoxic sAβs. Importantly, the enhanced autophagy also significantly suppresses the secretion of inflammatory factors by microglia, which is induced by internalized sAβs. Given that cerebral persistent inflammatory environment disturbs microglia-mediated phagocytosis and degradation, it is believed that this synergistic approach has valuable potential as a therapeutic strategy for AD.

Interplays between different secretases in the generation of Amyloid-[formula omitted] lead to the emergence of ‘Amyloid-[formula omitted] rise’

The abnormal accumulation of Amyloid-β (Aβ) initials the pathological progress of Alzheimer’s disease (AD). γ-secretase, which is a key secretase involving in the formation of Aβ, becomes one of candidate therapeutic targets for preventing the pathological progress of AD. In order to reduce the amount of Aβ in brain, different types of γ-secretase inhibitor were designed to limit the catalytic rate of γ-secretase. However, there is a paradoxical phenomenon called ‘Aβ rise’ can be found in experiment. In this phenomenon, the amount of Aβ will rise as the lower levels of γ-secretase inhibitor is added, which hinders the development of related drugs. In present paper, a mathematical model based on the generation of Aβ is proposed to explore the biological mechanism of ‘Aβ rise’. Through rigorous analysis about the dynamic behavior for this model, we firstly obtain the index for the emergence of ‘Aβ rise’. Furthermore, the analysis results show that both the inhibition of C-terminal fragment (C99) to α-secretase cleavage of amyloid precursor protein (APP) and the lower γ-secretase independent degradation for C99 are contributed to ‘Aβ rise’. Hence, enhancing the intensity of γ-secretase independent degradation of C99 can effectively block the appearance of ‘Aβ rise’. These findings will give new insights on the arise of ‘Aβ rise’ and therapeutic strategies for AD.

MALDI mass spectrometry imaging discloses the decline of sulfoglycosphingolipid and glycerophosphoinositol species in the brain regions related to cognition in a mouse model of Alzheimer's disease

Aging and neurodegenerative disease are accompanied by lipid perturbations in the brain. Understanding the changes in the contents and functional activity of lipids remains a challenge not only because of the many areas in which lipids perform bioactivities but also because of the technical limitations in identifying lipids and their metabolites. In the present study, we aimed to evaluate how brain lipids are altered in Alzheimer's disease (AD)-like pathology by using mass spectrometry imaging (MSI). The spatial distributions and relative abundances of lipids in the brains were compared between APP/PS1 mice and their age-matched wild-type (WT) mice by matrix-assisted laser desorption ionization (MALDI) MSI assays. The comparisons were correlated with the analysis using a spectrophotometric method to determine the relative contents of sulfatides in different brain regions. Significant changes of brain lipids between APP/PS1 and WT mice were identified: eight sulfoglycosphingolipid species, namely, sulfatides/sulfated hexosyl ceramides (ShexCer) and two glycerophosphoinositol (GroPIn) species, PI 36:4 and PI 38:4. The declines in the spatial distributions of these ShexCer and GroPIn species in the APP/PS1 mice brains were associated with learning- and memory-related brain regions. Compared with young WT mice, aged WT mice showed significant decreases in the levels of these ShexCer and GroPIn species. Our results provide technical clues for assessing the impact of brain lipid metabolism on the senescent and neurodegenerative brain. The decline in sulfatides and GroPIns may be crucial markers during brain senescence and AD pathology. Appropriate lipid complementation might be important potentials as a therapeutic strategy for AD.

Enhancement of neural regeneration as a therapeutic strategy for Alzheimer's disease (Review).

Alzheimer's disease (AD), the most common cause of dementia worldwide, has gradually become a global health concern for society and individuals with the process of global ageing. Although extensive research has been carried out on AD, the etiology and pathological mechanism of the disease are still unclear, and there is no specific drug to cure or delay AD progression. The exploration of enhancing nerve regeneration in AD has gradually attracted increasing attention. In the current review, the existing therapeutic strategies were summarized to induce nerve regeneration which can increase the number of neurons, and improve the survival of neurons, the plasticity of synapses and synaptic activity. The strategies include increasing neurotrophic expression (such as brain-derived neurotrophic factor and nerve growth factor), inhibiting acetylcholinesterase (such as donepezil, tacrine, rivastigmine and galanthamine), elevating histone deacetylase levels (such as RGFP-966, Tasquinimod, CM-414 and 44B), stimulating the brain by physiotherapy (such as near-infrared light, repetitive transcranial magnetic stimulation, and transcranial direct current stimulation) and transplanting exogenous neural stem cells. However, further evaluations need to be performed to determine the optimal treatment. The present study reviews recent interventions for enhancing adult neurogenesis and attempts to elucidate their mechanisms of action, which may provide a theoretical basis for inducing nerve regeneration to fight against AD.

The Sigma Receptors in Alzheimer's Disease: New Potential Targets for Diagnosis and Therapy.

Sigma (σ) receptors are a class of unique proteins with two subtypes: the sigma-1 (σ1) receptor which is situated at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), and the sigma-2 (σ2) receptor, located in the ER-resident membrane. Increasing evidence indicates the involvement of both σ1 and σ2 receptors in the pathogenesis of Alzheimer's disease (AD), and thus these receptors represent two potentially effective biomarkers for emerging AD therapies. The availability of optimal radioligands for positron emission tomography (PET) neuroimaging of the σ1 and σ2 receptors in humans will provide tools to monitor AD progression and treatment outcomes. In this review, we first summarize the significance of both receptors in the pathophysiology of AD and highlight AD therapeutic strategies related to the σ1 and σ2 receptors. We then survey the potential PET radioligands, with an emphasis on the requirements of optimal radioligands for imaging the σ1 or σ2 receptors in humans. Finally, we discuss current challenges in the development of PET radioligands for the σ1 or σ2 receptors, and the opportunities for neuroimaging to elucidate the σ1 and σ2 receptors as novel biomarkers for early AD diagnosis, and for monitoring of disease progression and AD drug efficacy.