Role In Alzheimer's Disease Research Articles

Acetylcholinesterase – glucose-regulated protein 78 binding site prediction, a hope to cure neurological disorders such as Alzheimer’s disease

Cerebral amyloid plaques in the brain define the elderly neuralgic disorder, Alzheimer’s disease (AD). The enzyme Acetylcholinesterase (AChE) was reported to play a vital role in AD. It was shown that AChE induces amyloid fibril formation forming highly toxic AChE-Amyloid-β (Aβ) complexes. AChE can accelerate amyloid formation, and its inhibition could prevent such alterations to the enzyme. Understanding the proteostasis of AChE and its binding site to cellular chaperone GRP78 (Glucose-regulated protein 78) would help find a treatment for AD. In this study, the state of the art computational tools were utilized to predict the binding location of AChE that can stably associate with the cellular chaperone, GRP78. Sequence comparison along with molecular docking predicts two binding locations on AChE (C69–C96 and C257–C272) that could bind to GRP78 substrate binding domain β (SBDβ). The analysis of the docking data suggests that the former location has the best average binding affinity value (-12.16 kcal/mol) and average interaction pattern (13.9 ± 3.5 H-bonds, 5.5 ± 1.4 hydrophobic contacts, and 1.4 ± 1.2 salt bridges).

A microglia-containing 3D human brain organoid for studying HSV-1-induced Alzheimer’s disease

As a progressive neurodegenerative disorder, Alzheimer’s disease (AD) can result in significant memory loss and cognitive deterioration. Several recent studies show that herpes simplex virus type I (HSV-1) is closely related to AD pathology. Microglia, the primary immune cells in the central nervous system, are also shown to play an important role in AD. In this study, we developed a microglia-containing 3-dimensional (3D) human brain organoid from human-induced pluripotent stem cells (hiPSCs) to study the relationship between microglia and HSV-1-induced AD phenotypes. We found that microglia increased the generation of amyloid-β protein (Aβ) and neurofibrillary tangles (NFTs), contributed to neural loss, and enhanced gliosis and neuroinflammation. We also employed shRNA vectors to inhibit certain cytokines related to neuroinflammation and examined the impact on Aβ aggregation. This model can facilitate future research on the treatment of AD regarding microglia and HSV-1.

Identification of Phytoconstituents from Natural Product Database as SIRT2 Inhibitors for Potential Role in Alzheimer's Disease: An In-Silico Screening.

We aimed to conduct in silico screening of the potential phytoconstituent from a natural product database to find SIRT2 inhibitors. Alzheimer's disease (AD) is the most prevalent type of dementia, characterized by behavioral and mental symptoms as well as a progressive loss of cognitive ability. Since SIRT2 may be detrimental to neurological illnesses, it is a prime target for research into SIRT2 inhibitors. To identify the SIRT2 inhibitors and their role in AD. We have utilized NPAtlas database and screened using pharmacophore-based virtual screening, molecular docking, and simulation. The Natural Products Atlas provides unrestricted access to various natural products derived from bacteria and fungi, allowing researchers to investigate and visualize the extensive chemical diversity in the natural world. From in silico screening data, we have found phytoconstituents that could function as SIRT2 inhibitors. Six phytoconstituents were identified using pharmacophore-based virtual screening. According to molecular docking, Kurasoin B outperformed the reference molecule regarding binding energy. Kurasoin B exhibited a binding affinity of -12.543 kcal/mol, whereas the binding affinity of the reference molecule was -12.089 kcal/mol. The Kurasoin B complex with SIRT2 was determined to be stable throughout the simulation by performing MD simulation, with an RMSD of 2.88 (Å), whereas the reference and free protein displayed RMSDs of 3.74 and 4.70 (Å), respectively. In silico studies and data analysis, suggest that Kurasoin B may be able to suppress the SIRT2 protein for managing AD.

Gut microbiome-derived metabolites in Alzheimer's disease: Regulation of immunity and potential for therapeutics.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and cause of dementia. Despite the prevalence of AD, there is a lack of effective disease modifying therapies. Recent evidence indicates that the gut microbiome (GMB) may play a role in AD through its regulation of innate and adaptive immunity. Gut microbes regulate physiology through their production of metabolites and byproducts. Microbial metabolites may be beneficial or detrimental to the pathogenesis and progression of inflammatory diseases. A better understanding of the role GMB-derived metabolites play in AD may lead to the development of therapeutic strategies for AD. In this review, we summarize the function of bioactive GMB-derived metabolites and byproducts and their roles in AD models. We also call for more focus on this area in the gut-brain axis field in order to create effective therapies for AD.

Early wave reflection of carotid artery is associated with 18F-FDG PET hypometabolism in Alzheimer's brain areas of cognitively normal adults.

Arterial stiffening likely plays a role in Alzheimer disease (AD) pathogenesis. The current study investigated whether inter-individual variations in arterial stiffness and pressure wave parameters were associated with 18F-FDG positron emission tomography (PET) metabolism in AD-associated brain areas throughout adulthood, independently of age and before the onset of any neuropsychological disorders. A prospective, large age-range population of 67 patients (17 young, 16 middle-aged, and 34 older adults; 37 women) underwent a: brain 18F-FDG PET, blood pressure recording, and carotid/femoral pulse wave-based measurements, including the time-to-peak of the reflected backward carotid pulse wave (bT), on the same day. Multivariable and quantitative voxel-to-voxel analyses (P-voxel < 0.005, corrected for cluster volumes) were conducted to assess associations between vascular parameters and 18F-FDG PET metabolism in AD-associated brain areas. In the multivariable analysis, only increased age and decreased bT were independently associated with the decline of metabolic activity in AD-associated brain areas (P < 0.001). In the voxel-to-voxel analysis with age as a covariate, bT was strongly associated with the metabolic activity of 40 clusters in AD-associated brain areas (clusters cumulative volume: 63 cm3; T score max: 5.7). In a large age-range population of adult patients, who are still unaffected by neuropsychological disorders, an early reflected arterial pressure wave, as evidenced by a decreased bT value, is strongly associated with hypometabolic activity of AD-associated brain areas, independently of age.

Neobavaisoflavone Ameliorates Memory Deficits and Brain Damage in Aβ25-35-Induced Mice by Regulating SIRT1.

Alzheimer's disease (AD) is a common chronic neurodegenerative disease in older people, and there is no specific treatment that can stop or reverse its progression. Neobavaisoflavone (NBIF) is a flavonoid that has been shown to have neuroprotective effects, but its role in AD has not been revealed. The present study investigated the role and mechanism of NBIF on Aβ25-35-induced brain injury. In this experiment, the AD mouse model was established by injection of Aβ25-35 peptides (200 μM, icv), and Donepezil (Don, 10 mg/kg/days), NBIF-L (15 mg/kg/days), and NBIF-H (30 mg/kg/days) were administered orally for 4 weeks. Learning memory, hippocampal pathological changes, pathological markers, apoptosis, oxidative stress, inflammation, immune cells were measured in mice. Network pharmacology combined with the GEO database led to the identification of SIRT1, a key target for NBIF intervention in AD, and levels of SIRT1, p-STAT3 and FOXO1 were measured. In addition, the antagonistic activity of SIRT1 transfection silencing against NBIF in Aβ25-35-induced in N9 cells and N2a-APP69 cells was investigated to assess whether the effects caused by NBIF were mediated by SIRT1. The results showed that NBIF ameliorated learning memory and hippocampal neuronal damage, reduced pathological markers, apoptosis, oxidative stress and neuroinflammation, and modulated immune cells. SIRT1 is a key target for NBIF intervention in AD, and NBIF upregulates SIRT1 and reduces the expression levels of p-STAT3 and FOXO1. Furthermore, silencing SIRT1 effectively reduced the protective effect of NBIF on Aβ25-35-induced N9 cells and N2a-APP69 cells, which indicated that the protective effect of NBIF on AD is related to SIRT1. NBIF ameliorated Aβ25-35-induced brain injury by inhibiting apoptosis, oxidative stress, and neuroinflammation, which may be mediated through SIRT1 signaling. These findings provide a rationale for NBIF in the treatment of AD and help facilitate the development of clinical therapeutic agents for AD.

Altered copper transport in oxidative stress-dependent brain endothelial barrier dysfunction associated with Alzheimer's disease

Oxidative stress and blood-brain barrier (BBB) disruption due to brain endothelial barrier dysfunction contribute to Alzheimer's Disease (AD), which is characterized by beta-amyloid (Aβ) accumulation in senile plaques. Copper (Cu) is implicated in AD pathology and its levels are tightly controlled by several Cu transport proteins. However, their expression and role in AD, particularly in relation to brain endothelial barrier function remains unclear. In this study, we examined the expression of Cu transport proteins in the brains of AD mouse models as well as their involvement in Aβ42-induced brain endothelial barrier dysfunction. We found that the Cu uptake transporter CTR1 was upregulated, while the Cu exporter ATP7A was downregulated in the hippocampus of AD mouse models and in Aβ42-treated human brain microvascular endothelial cells (hBMECs). In the 5xFAD AD mouse model, Cu levels (assessed by ICP-MS) were elevated in the hippocampus. Moreover, in cultured hBMECs, Aβ42-induced reactive oxygen species (ROS) production, ROS-dependent loss in barrier function (measured by transendothelial electrical resistance), and tyrosine phosphorylation of CDH5 were all inhibited by either a membrane permeable Cu chelator or by knocking down CTR1 expression. These findings suggest that dysregulated expression of Cu transport proteins may lead to intracellular Cu accumulation in the AD brain, and that Aβ42 promotes ROS-dependent brain endothelial barrier dysfunction and CDH5 phosphorylation in a CTR1-Cu-dependent manner. Our study uncovers the critical role of Cu transport proteins in oxidative stress-related loss of BBB integrity in AD.

Microglial Drivers of Alzheimer's Disease Pathology: AnEvolution of Diverse Participating States.

Microglia, the resident immune-competent cells of the brain, become dysfunctional in Alzheimer's disease (AD), and their aberrant immune responses contribute to the accumulation of pathological proteins and neuronal injury. Genetic studies implicate microglia in the development of AD, prompting interest in developing immunomodulatory therapies to prevent or ameliorate disease. However, microglia take on diverse functional states in disease, playing both protective and detrimental roles in AD, which largely overlap and may shift over the disease course, complicating the identification of effective therapeutic targets. Extensive evidence gathered using transgenic mouse models supports an active role of microglia in pathology progression, though results vary and can be contradictory between different types of models and the degree of pathology at the time of study. Here, we review microglial immune signaling and responses that contribute to the accumulation and spread of pathological proteins or directly affect neuronal health. We additionally explore the use of induced pluripotent stem cell (iPSC)-derived models to study living human microglia and how they have contributed to our knowledge of AD and may begin to fill in the gaps left by mouse models. Ultimately, mouse and iPSC-derived models have their own limitations, and a comprehensive understanding of microglial dysfunction in AD will only be established by an integrated view across models and an appreciation for their complementary viewpoints and limitations.

Causal Effects of Kidney Function and Chronic Kidney Disease on Alzheimer's Disease by Analyzing Large-Scale Genome-Wide Association Study Datasets.

Alzheimer's disease (AD) is the leading cause of dementia. Genetic components play an important role in AD and have been widely evaluated by genome-wide association studies (GWAS) and exome sequencing, and some common and rare genetic variants have been identified. In addition to genetic factors, environment factors have a role in AD. Growing evidence from observational studies linked impaired kidney function to cognitive impairment and AD; however, there are inconsistences in these findings. To determine the causal effects of impaired kidney function and chronic kidney disease (CKD) on AD. Mendelian randomization (MR) methods have been widely used to infer causal associations between exposure and outcome. Here, we conducted an MR study to investigate the causal effects of impaired kidney function and CKD on the risk of AD by analyzing large-scale GWAS datasets from FinnGen and CKD Genetics (CKDGen) Consortium. We found no significant but a suggestive effect of CKD on decreased risk of AD using inverse-variance weighted (IVW) (p = 8.46E-02) and simple mode (p = 7.60E-02) methods. We identified a statistically significant effect of the estimated glomerular filtration rate (eGFR) on increased risk of AD using IVW (p = 1.11E-02), weighted median regression (p = 5.60E-03), and weighted mode (p = 2.45E-02) methods. Together, our findings indicate that high eGFR levels may increase the risk of AD. These findings need to be verified in future studies.

ABCA7-dependent induction of neuropeptide Y is required for synaptic resilience in Alzheimer’s disease through BDNF/NGFR signaling

Genetic variants in ABCA7, an Alzheimer's disease (AD)-associated gene, elevate AD risk, yet its functional relevance to the etiology is unclear. We generated a CRISPR-Cas9-mediated abca7 knockout zebrafish to explore ABCA7's role in AD. Single-cell transcriptomics in heterozygous abca7+/- knockout combined with Aβ42 toxicity revealed that ABCA7 is crucial for neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), and nerve growth factor receptor (NGFR) expressions, which are crucial for synaptic integrity, astroglial proliferation, and microglial prevalence. Impaired NPY induction decreased BDNF and synaptic density, which are rescuable with ectopic NPY. In induced pluripotent stem cell-derived human neurons exposed to Aβ42, ABCA7-/- suppresses NPY. Clinical data showed reduced NPY in AD correlated with elevated Braak stages, genetic variants in NPY associated with AD, and epigenetic changes in NPY, NGFR, and BDNF promoters linked to ABCA7 variants. Therefore, ABCA7-dependent NPY signaling via BDNF-NGFR maintains synaptic integrity, implicating its impairment in increased AD risk through reduced brain resilience.

Active Site Environment and Reactivity of Copper-Aβ in Membrane Mimetic SDS Micellar Environment.

Alzheimer's disease (AD) is characterized by the abnormal aggregation of amyloid β (Aβ) peptide in extracellular deposits generated upon proteolysis of Amyloid Precursor Protein (APP). While copper (Cu(II)) binds to Aβ in soluble oligomeric and aggregated forms, its interaction with membrane-bound Aβ remains elusive. Investigating these interactions is crucial for understanding AD pathogenesis. Here, utilizing SDS micelles as a simplified membrane mimic, we focus on elucidating the interplay between membrane-anchored Aβ and copper, given their pivotal roles in AD. We employed spectroscopic techniques including UV, CD, and EPR to characterize the active site of Cu-Aβ complexes. Our findings demonstrate that copper interacts with Aβ peptides in membrane-mimicking micellar environments similarly to aqueous buffer solutions. Cu-Aβ complexes in this medium also induce higher hydrogen peroxide (H2O2) production, potentially contributing to AD-related oxidative stress. Moreover, we observe an increased oxidation rate of neurotransmitter such as dopamine by Cu-Aβ complexes. These results enhance our understanding of Cu-Aβ interactions in AD pathology and offer insights into potential therapeutic interventions targeting this interaction.

Oleanonic acid ameliorates mutant Aβ precursor protein-induced oxidative stress, autophagy deficits, ferroptosis, mitochondrial damage, and ER stress in vitro

Accumulation in the brain of amyloid-β (Aβ), derived from cleavage of Aβ precursor protein (APP), is a hallmark of Alzheimer's disease (AD). Oleanonic acid (OA), a phytochemical from several plants, has proven anti-inflammatory effects, but its role in AD remains unknown. Here we found that OA reduced APP expression and inhibited oxidative stress via Nrf2/HO-1 signaling in SH-SY5Y neuroblastoma cells stably overexpressing APP. OA suppressed phosphorylated mTOR but increased autophagy markers ATG5 and LC3-II. Moreover, OA rescued ferroptosis-related factors GPX4, NCOA, and COX2 and ER stress markers GRP78, CHOP, and three main induction pathways of ER stress including IRE1/XBP1s, PERK/EIF2α, and ATF6. OA alleviated mitochondrial damage through MFN1, MFN2, OPA1, FIS1, and DRP1. Furthermore, OA upregulated GDF11 expression and downregulated phosphorylation of ErbB4 and TrkB without affecting BDNF levels. Thus, OA might protect neurons from APP-induced neurotoxicity by inhibiting oxidative stress, autophagy deficits, ferroptosis, mitochondrial damage, and ER stress in AD, providing a new promising therapeutic strategy in patients with AD.

Plant extracts as emerging modulators of neuroinflammation and immune receptors in Alzheimer's pathogenesis

Memory loss is becoming an increasingly significant health problem, largely due to Alzheimer's disease (AD), which disrupts the brain in several ways, including causing inflammation and weakening the body's defenses. This study explores the potential of medicinal plants as a source of novel therapeutic agents for AD.First, we tested various plant extracts against acetylcholinesterase (AChE) in vitro, following molecular docking simulations with key AD-related protein targets such as MAO-B, P-gp, GSK-3β, and CD14. Rosemary extract was found to be the most inhibitory towards AChE. The compounds found in rosemary (oleanolic acid), sage (pinocembrin), and cinnamon (italicene) showed promise in potentially binding to MAO-B. These chemicals may interact with a key protein in the brain and alter the production and removal of amyloid-β. Luteolin (from rosemary), myricetin (from sage), chamigrene, and italicene (from cinnamon) exhibited potential for inhibiting tau aggregation. Additionally, ursolic acid found in rosemary, sage, and chamigrene from cinnamon could modulate CD14 activity.For the first time, our findings shed light on the intricate interplay between neuroinflammation, neuroprotective mechanisms, and the immune system's role in AD. Further research is needed to validate the in vivo efficacy and safety of these plant-derived compounds, as well as their interactions with key protein targets, which could lead to the development of novel AD therapeutics.

Role of short chain fatty acids on astrocytes and microglia in Alzheimer's disease brain

SummaryShort‐chain fatty acids (SCFAs) hold exert many nutritional benefits on both physiological and pathological processes, including host metabolism, immune modulation, and appetite control. Originating from the microbial fermentation of resistant starches and dietary fibre in the colon, SCFAs have the capability to traverse the blood–brain barrier (BBB). It is evident that SCFAs play a critical role in the development of neurodegenerative disorders such as Alzheimer's disease (AD). AD is the most common form of dementia and is characterised by the deposition of amyloid β peptides (Aβ) and tau hyperphosphorylation. SCFAs have demonstrated the potential to interfere with the protein–protein interactions required for Aβ peptides to form neurotoxic oligomers. Moreover, research indicates that the SCFAs ability to maintain endothelial integrity and interact with neuroglial cells through the BBB may assist in downregulating excessive neuroinflammatory responses to amyloid peptides. This review summarises the research on SCFAs' potential role in AD and understand their mechanism of actions on astrocytes and microglia.

Selenoprotein W modulates tau homeostasis in an Alzheimer’s disease mouse model

Lower selenium levels are observed in Alzheimer’s disease (AD) brains, while supplementation shows multiple benefits. Selenoprotein W (SELENOW) is sensitive to selenium changes and binds to tau, reducing tau accumulation. However, whether restoration of SELENOW has any protective effect in AD models and its underlying mechanism remain unknown. Here, we confirm the association between SELENOW downregulation and tau pathology, revealing SELENOW’s role in promoting tau degradation through the ubiquitin‒proteasome system. SELENOW competes with Hsp70 to interact with tau, promoting its ubiquitination and inhibiting tau acetylation at K281. SELENOW deficiency leads to synaptic defects, tau dysregulation and impaired long-term potentiation, resulting in memory deficits in mice. Conversely, SELENOW overexpression in the triple transgenic AD mice ameliorates memory impairment and tau-related pathologies, featuring decreased 4-repeat tau isoform, phosphorylation at Ser396 and Ser404, neurofibrillary tangles and neuroinflammation. Thus, SELENOW contributes to the regulation of tau homeostasis and synaptic maintenance, implicating its potential role in AD.

An Expanded Narrative Review of Neurotransmitters on Alzheimer's Disease: The Role of Therapeutic Interventions on Neurotransmission.

Alzheimer's disease (AD) is a progressive neurodegenerative disease. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles are the key players responsible for the pathogenesis of the disease. The accumulation of Aβ plaques and tau affect the balance in chemical neurotransmitters in the brain. Thus, the current review examined the role of neurotransmitters in the pathogenesis of Alzheimer's disease and discusses the alterations in the neurochemical activity and cross talk with their receptors and transporters. In the presence of Aβ plaques and neurofibrillary tangles, changes may occur in the expression of neuronal receptors which in turn triggers excessive release of glutamate into the synaptic cleft contributing to cell death and neuronal damage. The GABAergic system may also be affected by AD pathology in a similar way. In addition, decreased receptors in the cholinergic system and dysfunction in the dopamine neurotransmission of AD pathology may also contribute to the damage to cognitive function. Moreover, the presence of deficiencies in noradrenergic neurons within the locus coeruleus in AD suggests that noradrenergic stimulation could be useful in addressing its pathophysiology. The regulation of melatonin, known for its effectiveness in enhancing cognitive function and preventing Aβ accumulation, along with the involvement of the serotonergic system and histaminergic system in cognition and memory, becomes remarkable for promoting neurotransmission in AD. Additionally, nitric oxide and adenosine-based therapeutic approaches play a protective role in AD by preventing neuroinflammation. Overall, neurotransmitter-based therapeutic strategies emerge as pivotal for addressing neurotransmitter homeostasis and neurotransmission in the context of AD. This review discussed the potential for neurotransmitter-based drugs to be effective in slowing and correcting the neurodegenerative processes in AD by targeting the neurochemical imbalance in the brain. Therefore, neurotransmitter-based drugs could serve as a future therapeutic strategy to tackle AD.

Insulin resistance as the molecular link between diabetes and Alzheimer's disease.

Diabetes mellitus (DM) and Alzheimer's disease (AD) are two major health concerns that have seen a rising prevalence worldwide. Recent studies have indicated a possible link between DM and an increased risk of developing AD. Insulin, while primarily known for its role in regulating blood sugar, also plays a vital role in protecting brain functions. Insulin resistance (IR), especially prevalent in type 2 diabetes, is believed to play a significant role in AD's development. When insulin signalling becomes dysfunctional, it can negatively affect various brain functions, making individuals more susceptible to AD's defining features, such as the buildup of beta-amyloid plaques and tau protein tangles. Emerging research suggests that addressing insulin-related issues might help reduce or even reverse the brain changes linked to AD. This review aims to explore the rela-tionship between DM and AD, with a focus on the role of IR. It also explores the molecular mechanisms by which IR might lead to brain changes and assesses current treatments that target IR. Understanding IR's role in the connection between DM and AD offers new possibilities for treatments and highlights the importance of continued research in this interdisciplinary field.

Targeting zincosomes to unveil lysosomal zinc ion dynamics and their role in exacerbating Alzheimer's pathology

Maintaining lysosomal zinc (Zn2+) homeostasis is crucial for cellular functionality, with its dysregulation implicated in the progression of neurodegenerative disorders, notably Alzheimer's disease (AD). The paucity of effective tools for precise lysosomal Zn2+ visualization has been a significant barrier to elucidating its role in AD. In response, a highly sensitive and selective novel fluorescent probe based on a salicylaldehyde Schiff base derivative, SSb, was developed to visualize Zn2+ dynamics. Our findings unveil a previously uncharacterized Zn2+ transport mechanism via zincosomes, highlighting their engulfment by mitochondria during autophagy, facilitated by SSb. Significantly, Zn2+ levels were found to be elevated in the brains of AD model mice, associated with amyloid-β (Aβ) deposits. Additionally, our study indicates an abnormal activation of autophagy in AD models, suggesting that Zn2+ increment may exacerbate AD pathology by fostering Aβ deposition and toxicity. This investigation provides valuable insights into Zn2+ homeostasis and its impact on AD, laying the groundwork for novel diagnostic and therapeutic avenues in combating AD, further reflecting the interdisciplinary nature of chemical engineering and biomedical research.

Reduced platelet activation and thrombus formation in male transgenic model mice of Alzheimer's disease suggests early sex-specific differences in platelet pathophysiology

Alzheimer's disease (AD) is the most common form of dementia and characterized by extracellular amyloid-β (Aβ) plaques, intracellular neurofibrillary tau tangles and neurodegeneration. Over 80 % of AD patients also exhibit cerebral amyloid angiopathy (CAA). CAA is a cerebrovascular disease caused by deposition of Aβ in the walls of cerebral blood vessels leading to vessel damage and impairment of normal blood flow. To date, different studies suggest that platelet function, including activation, adhesion and aggregation, is altered in AD due to vascular Aβ deposition. For example, the transgenic AD model mice APP23 mice that exhibit CAA and parenchymal Aβ plaques, show pre-activated platelets in the blood circulation and increased platelet integrin activation leading to a pro-thrombotic phenotype in these mice late stages of AD. However, it is still an open question whether or not platelets exhibit changes in their activation profile before they are exposed to vascular Aβ deposits. Therefore, the present study examined platelets from middle-aged transgenic APP23 mice at the age of 8–10 months. At this age, APP23 mice show amyloid plaques in the brain parenchyma but not in the vasculature. Our analyses show that these APP23 mice have unaltered platelet numbers and size, and unaltered surface expression of glycoproteins. However, the number of dense granules in transgenic platelets was increased while the release was unaltered. Male, but not female APP23 mice, exhibited reduced platelet activation after stimulation of the thrombin receptor PAR4 and decreased thrombus stability on collagen under flow conditions ex vivo compared to control mice. In an arterial thrombosis model in vivo, male APP23 mice showed attenuated occlusion of the injured artery compared to controls. These findings provide clear evidence for early changes in platelet activation and thrombus formation in male mice before development of overt CAA. Furthermore, reduced platelet activation and thrombus formation suggest sex-specific differences in platelet physiology in AD that has to be considered in future studies of platelets and their role in AD.

Thioredoxin-1 Protects Neurons Through Inhibiting NLRP1-Mediated Neuronal Pyroptosis in Models of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease all over the world. In the last decade, accumulating proofs have evidenced that neuroinflammation is intimately implicated in the pathogenesis of AD and activation of NOD-like receptor family pyrin domain-containing 1 (NLRP1) inflammasome can induce neuronal pyroptosis and in turn lead to neuronal loss in AD. Thioredoxin-1 (Trx-1), a multifunctional molecule with anti-inflammation in human tissues, displays crucial neuroprotective roles in AD. Our previous research preliminarily found that Trx-1 inhibition enhanced the expression of NLRP1, caspase-1, and gasdermin D (GSDMD) in Aβ25-35-treated PC12 cells. However, it is largely unknown if Trx-1 can inhibit NLRP1-mediated neuronal pyroptosis in AD neurons. In this study, it was verified that the protein levels of NLRP1, caspase-1, and GSDMD were significantly increased in Aβ25-35-treated mouse HT22 and primary hippocampal neurons. Suppression of Trx-1 with PX-12, a selective inhibitor of Trx-1, or Trx-1 knockdown further activated NLRP1-mediated neuronal pyroptosis. On the contrary, lentivirus infection-mediated Trx-1 overexpression in differentiated PC12 cells dramatically reversed expression of NLRP1, caspase-1, and GSDMD. Furthermore, Trx-1 overexpression mediated by adeno-associated virus in the hippocampal tissues of APP/PS1 mice likewise attenuated the activation of NLRP1-mediated neuronal pyroptosis, as well as reduced the hippocampal deposition of Aβ and ameliorated the cognitive function of APP/PS1 mice. In conclusion, this article predicates a novel molecular mechanism by which Trx-1 exploits neuroprotection through attenuating NLRP1-mediated neuronal pyroptosis in AD models, suggesting that Trx-1 may be a promising therapeutic target for AD.