Intracranial arteriosclerosis is not associated with cerebral amyloid deposition.

BACKGROUND: Intracranial arteriosclerosis and cerebral amyloid beta (Aß) are both involved in the etiology of Alzheimer's disease (AD) dementia, but the direct link between these two pathologies remains elusive. METHODS: In 633 participants (mean age 69 years, 51% women) from the population-based Rotterdam Study, we quantified cerebral Aß accumulation on amyloid positron emission tomography (PET). We assessed calcification of the intracranial internal carotid (ICAC) and vertebrobasilar arteries (VBAC) as proxies of arteriosclerosis on non-enhanced computed tomography (CT). Using logistic and linear regression, we studied the relationship of presence, burden, and type of calcification with the presence and burden of Aß. RESULTS: We found no associations of ICAC [odds ratio (OR): 0.85, 95% confidence interval (CI): 0.43, 1.72] or VBAC [OR: 0.59, CI: 0.26, 1.24] with cerebral Aß. The results did not vary across ICAC subtypes. DISCUSSION: Intracranial arteriosclerosis was not associated with cerebral Aß, underscoring their independence in the etiology of AD dementia. Highlights: Comprehensive assessment of intracranial arteriosclerosis (e.g., including subtypes).Intracranial arteriosclerosis in different arteries and cerebral Aß are not related.Arteriosclerosis and Aß likely influence Alzheimer's disease dementia independently.

The intricate interplay between microglia and adult neurogenesis in Alzheimer's disease.

Microglia, the resident immune cells of the central nervous system, play a crucial role in regulating adult neurogenesis and contribute significantly to the pathogenesis of Alzheimer's disease (AD). Under physiological conditions, microglia support and modulate neurogenesis through the secretion of neurotrophic factors, phagocytosis of apoptotic cells, and synaptic pruning, thereby promoting the proliferation, differentiation, and survival of neural progenitor cells (NPCs). However, in AD, microglial function becomes dysregulated, leading to chronic neuroinflammation and impaired neurogenesis. This review explores the intricate interplay between microglia and adult neurogenesis in health and AD, synthesizing recent findings to provide a comprehensive overview of the current understanding of microglia-mediated regulation of adult neurogenesis. Furthermore, it highlights the potential of microglia-targeted therapies to modulate neurogenesis and offers insights into potential avenues for developing novel therapeutic interventions.

Recommendations for clinical implementation of blood-based biomarkers for Alzheimer's disease.

Blood-based biomarkers (BBM) for Alzheimer's disease (AD) are being increasingly used in clinical practice to support an AD diagnosis. In contrast to traditional diagnostic modalities, such as amyloid positron emission tomography and cerebrospinal fluid biomarkers, BBMs offer a more accessible and lower cost alternative for AD biomarker testing. Their unique scalability addresses the anticipated surge in demand for biomarker testing with the emergence of disease-modifying treatments (DMTs) that require confirmation of amyloid pathology. To facilitate the uptake of BBMs in clinical practice, The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to provide recommendations for two clinical implementational pathways for BBMs: one for current use for triaging and another for future use to confirm amyloid pathology. These pathways provide a standardized diagnostic approach with guidance on interpreting BBM test results. Integrating BBMs into clinical practice will simplify the diagnostic process and facilitate timely access to DMTs for eligible patients.

Can Targeted Protein Degradation Technology Provide a Potential Breakthrough in the Development of Anti-AD Drugs?

Recent advancements in Alzheimer's disease (AD) research have led to the approval of lecanemab and donanemab, highlighting the effectiveness of amyloid-beta (Aß) degradation as a treatment for AD. The prospect of small molecule Aß degraders as a potential treatment, which utilizes emerging targeted protein degradation technology, is exciting, given their ability to address some of the limitations of current therapies and their promising future in AD treatment. Despite facing challenges, these degraders are poised to become a future treatment option, harnessing scientific breakthroughs for more targeted and effective AD therapy.

Association of Anticoagulant Use With Hemorrhage Location and Etiology in Incident Spontaneous Intracerebral Hemorrhage.

BACKGROUND: It is unknown whether hypertensive microangiopathy or cerebral amyloid angiopathy (CAA) predisposes more to anticoagulant-associated intracerebral hemorrhage (AA-ICH). The purpose of our study was to determine whether AA-ICH is associated with lobar location and probable CAA. METHODS: This was a cross-sectional analysis of patients with first-ever spontaneous ICH admitted to a tertiary hospital in Boston, between 2008 and 2023. Univariable and multivariable logistic regression were used to investigate the association between anticoagulation use and both lobar hemorrhage location and probable CAA on magnetic resonance imaging (MRI) by Boston Criteria 2.0 or computed tomography by Simplified Edinburgh Criteria. RESULTS: A total of 1104 patients (mean [SD] age, 73 [12]; 499 females [45.0%]) were included. Of the 1104 patients, 268 (24.3%) had AA-ICH: 148 (55.2%) with vitamin K antagonists and 107 (39.9%) with direct oral anticoagulants. Brain MRI was performed in 695 (63.0%) patients. The proportion of patients with lobar hemorrhage was not different between those with and without AA-ICH (121/268 [45.1%] versus 424/836 [50.7%]; odds ratio [OR], 0.80 [95% CI, 0.61-1.05]; P=0.113). Patients with AA-ICH were less likely to have probable CAA on MRI (17/146 [11.6%] versus 127/549 [23.1%]; OR, 0.44 [95% CI, 0.25-0.75]; P=0.002) and probable CAA on MRI or computed tomography if MRI not performed (27/268 [10.0%] versus 200/836 [23.9%]; OR, 0.36 [95% CI, 0.23-0.55]; P<0.001). Among patients with AA-ICH, there were no differences in the proportion with lobar hemorrhage (63/148 [42.6%] versus 46/107 [43.0%]; OR, 1.02 [95% CI, 0.62-1.68]; P=0.946) or probable CAA on MRI (10/72 [13.9%] versus 7/69 [10.1%]; OR, 0.70 [95% CI, 0.25-1.96]; P=0.495) between vitamin K antagonists and direct oral anticoagulant users. CONCLUSIONS: AA-ICH was not associated with lobar hemorrhage location but was associated with reduced odds of probable CAA. These results suggest that hypertensive microangiopathy may predispose more toward incident AA-ICH than CAA and emphasize the importance of blood pressure control among anticoagulant users. These findings require replication in additional cohorts.

In-vitro Neuro-2a cytotoxicity analysis and molecular docking investigation on potential anti-amyloid agents from Adiantum lunulatum.

In neurodegenerative diseases, amyloid formation by some proteins cause neuronal damage and loss. To prevent this neuronal damage and loss certain pharmaceuticals are available. Many of these pharmaceuticals act on the neurodegenerative disease symptoms but not on the root cause. This study helps to detect more effective agents which directly act on the root cause and reduce the risk of neurodegenerative diseases. To identify new anti-amyloid agents, the folk medicinally important plant Adiantum lunulatum was collected, authenticated, dried, extracted with ethanol and analyzed by GC-MS method. The screening of the identified phytochemicals was done using the webservers swissADME and ProTox-II. In-vitro MTT assay using Neuro-2a cell lines was carried out to determine the cytotoxicity of the extract. The interactions of these phytochemicals with the amyloid forming peptides and proteins were predicted using the molecular docking tools such as AutoDock Vina and BIOVIA discovery studio visualizer 2020. Through GC-MS analysis, 18 different volatile phytochemicals were identified from the ethanol extract. From this, 7 phytochemicals were selected based on the computational non-toxicity prediction. In-vitro cytotoxicity analysis of the ethanol extract using Neuro-2a cell lines detected the IC50 value of 0.09 mg/ml. Of these, the phytochemical P1 (trans, trans-9, 12-Octadecadienoic acid, propyl ester) interacts with tau, and huntingtin proteins, P2 (2-Pentadecanone, 6, 10, 14-trimethyl-) interacts with prion protein. The phytochemicals P1, P3 (Ethyl oleate), P4 (Octadecanoic acid, ethyl ester), and P5 (Phytol) interact with acetylcholinesterase. P2, P4, P5 and P6 (Henicosanal), interact with BACE-1. The phytochemical P3 interacts with γ- Secretase. The interaction of P2 and P5 with BACE-1 and P3 with γ- Secretase show better inhibition in inhibitory constant (K i ) analysis. These phytochemicals have been predicted to show significant potential against the formation or breakdown of peptide/protein amyloids, and further in-vitro studies are necessary to develop them into anti-amyloid agents.

Clinical application of sparse canonical correlation analysis to detect genetic associations with cortical thickness in Alzheimer's disease.

Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cerebral cortex atrophy. In this study, we used sparse canonical correlation analysis (SCCA) to identify associations between single nucleotide polymorphisms (SNPs) and cortical thickness in the Korean population. We also investigated the role of the SNPs in neurological outcomes, including neurodegeneration and cognitive dysfunction. Methods: We recruited 1125 Korean participants who underwent neuropsychological testing, brain magnetic resonance imaging, positron emission tomography, and microarray genotyping. We performed group-wise SCCA in Aß negative (-) and Aß positive (+) groups. In addition, we performed mediation, expression quantitative trait loci, and pathway analyses to determine the functional role of the SNPs. Results: We identified SNPs related to cortical thickness using SCCA in Aß negative and positive groups and identified SNPs that improve the prediction performance of cognitive impairments. Among them, rs9270580 was associated with cortical thickness by mediating Aß uptake, and three SNPs (rs2271920, rs6859, rs9270580) were associated with the regulation of CHRNA2, NECTIN2, and HLA genes. Conclusion: Our findings suggest that SNPs potentially contribute to cortical thickness in AD, which in turn leads to worse clinical outcomes. Our findings contribute to the understanding of the genetic architecture underlying cortical atrophy and its relationship with AD.

Plasma Biomarkers of Alzheimer's Disease and Neurodegeneration According to Sociodemographic Characteristics and Chronic Health Conditions.

Ultrasensitive assays have been developed which enable biomarkers of Alzheimer's disease pathology and neurodegeneration to be measured in blood. These biomarkers can aid in diagnosis, and have been used to predict risk of cognitive decline and Alzheimer's disease. The ease and cost-effectiveness of blood collections means that these biomarkers could be applied more broadly in population-based screening, however it is critical to first understand what other factors could affect blood biomarker levels. The aim of this review was to determine the extent that sociodemographic, lifestyle and health factors have been associated with blood biomarkers of Alzheimer's disease and neuropathology. Of the 32 studies included in this review, all but one measured biomarker levels in plasma, and age and sex were the most commonly investigated factors. The most consistent significant findings were a positive association between age and neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), and females had higher GFAP than men. Apolipoprotein ε4 allele carriers had lower Aß42 and Aß42/40 ratio. Body mass index was negatively associated with GFAP and NfL, and chronic kidney disease with higher levels of all biomarkers. Too few studies have investigated other chronic health conditions and this requires further investigation. Given the potential for plasma biomarkers to enhance Alzheimer's disease diagnosis in primary care, it is important to understand how to interpret the biomarkers in light of factors that physiologically impact blood biomarker levels. This information will be critical for the establishment of reference ranges and thus the correct interpretation of these biomarkers in clinical screening.

Progress in the Treatment of Alzheimer's Disease Is Needed - Position Statement of European Alzheimer's Disease Consortium (EADC) Investigators.

ß-amyloid-targeting antibodies represent the first generation of effective causal treatment of Alzheimer's disease (AD) and can be considered historical research milestones. Their effect sizes, side effects, implementation challenges and costs, however, have stimulated debates about their overall value. In this position statement academic clinicians of the European Alzheimer's Disease Consortium (EADC) discuss the critical relevance of introducing these new treatments in clinical care now. Given the complexity of AD it is unlikely that molecular single-target treatments will achieve substantially larger effects than those seen with current ß-amyloid-targeting antibodies. Larger effects will most likely only be achieved incrementally by continuous optimization of molecular approaches, patient selection and combinations therapies. To be successful in this regard, drug development must be informed by the use of innovative treatments in real world practice, because full understanding of all facets of novel treatments requires experience and data of real-world care beyond those of clinical trials. Regarding the antibodies under discussion we consider their effects meaningful and potential side effects manageable. We assume that the number of eventually treated patient will only be a fraction of all early AD patients due to narrow eligibility criteria and barriers of access. We strongly endorse the use of these new compound in clinical practice in selected patients with treatment documentation in registries. We understand this as a critical step in advancing the field of AD treatment, and in shaping the health care systems for the new area of molecular-targeted treatment of neurodegenerative diseases.

Japanese Subgroup Analyses from EMERGE and ENGAGE, Phase 3 Clinical Trials of Aducanumab in Patients with Early Alzheimer's Disease.

BACKGROUND: Global prevalence and incidence of dementia continue to rise at a rapid rate. There is a need for new Alzheimer's disease (AD) treatments globally. Aducanumab is a human monoclonal antibody that selectively targets aggregated soluble amyloid beta oligomers and insoluble amyloid beta fibrils. In June 2021, aducanumab was approved by the US Food and Drug Administration for the treatment of AD under the accelerated approval pathway. OBJECTIVES: We evaluated the efficacy, safety, biomarker and pharmacokinetics (PK) of aducanumab in Japanese subgroups in EMERGE and ENGAGE studies. DESIGN: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early AD (mild cognitive impairment due to AD or mild AD dementia). SETTING: These studies involved 348 sites in 20 countries. PARTICIPANTS: Participants enrolled in Japan included 121 (7.4% of total 1638 in EMERGE) and 100 (6.1% of total 1647 in ENGAGE) patients (aged 50-85 years with confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to AD or mild AD dementia. INTERVENTION: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (6 or 10 mg/kg target dose) or placebo via IV infusion once every 4 weeks over 76 weeks. MEASUREMENTS: The primary outcome measure was change from baseline to Week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; biomarker endpoints (amyloid PET and plasma p-tau181); serum PK profiles and immunogenicity. RESULTS: Results from the Japanese subgroup analyses were generally consistent with those of the overall study population across endpoints, while a lower mean body weight (kg) and a smaller proportion of ApoE ε4 carriers were observed in the Japanese subgroup population. A treatment effect was observed in favor of aducanumab on the primary and secondary efficacy endpoints at Week 78 in EMERGE, but not ENGAGE. The incidence and type of adverse events in the Japanese subgroups were generally comparable to those observed in the overall study population; amyloid related imaging abnormalities (ARIA) were common treatment-related adverse events that appeared to be related to the aducanumab dose. ARIA incidence was generally lower in the Japanese subgroup compared with the overall population. Consistent with the overall data set, a robust dose-dependent decrease in amyloid beta levels as assessed with amyloid-PET and plasma p-tau181 was observed. Serum PK profiles and immunogenicity of aducanumab in Japanese population were consistent with the non-Japanese population. CONCLUSION: Efficacy, safety, biomarker, and PK profiles of aducanumab were consistent between the Japanese subgroup and the overall population. A positive treatment effect of aducanumab on efficacy endpoints was observed in EMERGE, but not in ENGAGE.

Continuous Associations between Remote Self-Administered Cognitive Measures and Imaging Biomarkers of Alzheimer's Disease.

BACKGROUND: Easily accessible and self-administered cognitive assessments that can aid early detection for Alzheimer's disease (AD) dementia risk are critical for timely intervention. OBJECTIVES/DESIGN: This cross-sectional study investigated continuous associations between Mayo Test Drive (MTD) - a remote, self-administered, multi-device compatible, web-based cognitive assessment - and AD-related imaging biomarkers. PARTICIPANTS/SETTING: 684 adults from the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer's Disease Research Center participated (age=70.4±11.2, 49.7% female). Participants were predominantly cognitively unimpaired (CU; 94.0%). MEASUREMENTS: Participants completed (1) brain amyloid and tau PET scans and MRI scans for hippocampal volume (HV) and white matter hyperintensities (WMH); (2) MTD remotely, consisting of the Stricker Learning Span and Symbols Test which combine into an MTD composite; and (3) in-person neuropsychological assessment including measures to obtain Mayo Preclinical Alzheimer's disease Cognitive Composite (Mayo-PACC) and Global-z. Multiple regressions adjusted for age, sex, and education queried associations between imaging biomarkers and scores from remote and in-person cognitive measures. RESULTS: Lower performances on MTD were associated with greater amyloid, entorhinal tau, and global tau PET burden, lower HV, and higher WMH. Mayo-PACC and Global-z were associated with all imaging biomarkers except global tau PET burden. MCI/Dementia participants showed lower performance on all MTD measures compared to CU with large effect sizes (Hedge's g's=1.65-2.02), with similar findings for CU versus MCI only (Hedge's g's=1.46-1.83). CONCLUSION: MTD is associated with continuous measures of AD-related imaging biomarkers, demonstrating ability to detect subtle cognitive change using a brief, remote assessment in predominantly CU individuals and criterion validity for MTD.

Subthreshold amyloid deposition, cerebral small vessel disease, and functional brain network disruption in delayed cognitive decline after stroke.

Background: Although its incidence is relatively low, delayed-onset post-stroke cognitive decline (PSCD) may offer valuable insights into the "vascular contributions to cognitive impairment and dementia," particularly concerning the roles of vascular and neurodegenerative mechanisms. We postulated that the functional segregation observed during post-stroke compensation could be disrupted by underlying amyloid pathology or cerebral small vessel disease (cSVD), leading to delayed-onset PSCD. Methods: Using a prospective stroke registry, we identified patients who displayed normal cognitive function at baseline evaluation within a year post-stroke and received at least one subsequent assessment. Patients suspected of pre-stroke cognitive decline were excluded. Decliners [defined by a decrease of ≥3 Mini-Mental State Examination (MMSE) points annually or an absolute drop of ≥5 points between evaluations, confirmed with detailed neuropsychological tests] were compared with age- and stroke severity-matched non-decliners. Index-stroke MRI, resting-state functional MRI, and 18F-florbetaben PET were used to identify cSVD, functional network attributes, and amyloid deposits, respectively. PET data from age-, sex-, education-, and apolipoprotein E-matched stroke-free controls within a community-dwelling cohort were used to benchmark amyloid deposition. Results: Among 208 eligible patients, 11 decliners and 10 matched non-decliners were identified over an average follow-up of 5.7 years. No significant differences in cSVD markers were noted between the groups, except for white matter hyperintensities (WMHs), which were strongly linked with MMSE scores among decliners (rho = -0.85, p < 0.01). Only one decliner was amyloid-positive, yet subthreshold PET standardized uptake value ratios (SUVR) in amyloid-negative decliners inversely correlated with final MMSE scores (rho = -0.67, p = 0.04). Decliners exhibited disrupted modular structures and more intermingled canonical networks compared to non-decliners. Notably, the somato-motor network's system segregation corresponded with the decliners' final MMSE (rho = 0.67, p = 0.03) and was associated with WMH volume and amyloid SUVR. Conclusion: Disruptions in modular structures, system segregation, and inter-network communication in the brain may be the pathophysiological underpinnings of delayed-onset PSCD. WMHs and subthreshold amyloid deposition could contribute to these disruptions in functional brain networks. Given the limited number of patients and potential residual confounding, our results should be considered hypothesis-generating and need replication in larger cohorts in the future.

Multifaceted neuroprotective approach of Trolox in Alzheimer's disease mouse model: targeting Aß pathology, neuroinflammation, oxidative stress, and synaptic dysfunction.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by the deposition of amyloid beta (Aß) plaques and neurofibrillary tangles (NFTs) in the brain. The accumulation of these aggregated proteins causes memory and synaptic dysfunction, neuroinflammation, and oxidative stress. This research study is significant as it aims to assess the neuroprotective properties of vitamin E (VE) analog Trolox in an Aß1 - 42-induced AD mouse model. Aß1 - 42 5µL/5min/mouse was injected intracerebroventricularly (i.c.v.) into wild-type adult mice brain to induce AD-like neurotoxicity. For biochemical analysis, Western blotting and confocal microscopy were performed. Remarkably, intraperitoneal (i.p.) treatment of Trolox (30 mg/kg/mouse for 2 weeks) reduced the AD pathology by reducing the expression of Aß, phosphorylated tau (p-tau), and ß-site amyloid precursor protein cleaving enzyme1 (BACE1) in both cortex and hippocampus regions of mice brain. Furthermore, Trolox-treatment decreased neuroinflammation by inhibiting Toll-like receptor 4 (TLR4), phosphorylated nuclear factor-κB (pNF-κB) and interleukin-1ß (IL-1ß), and other inflammatory biomarkers of glial cells [ionized calcium-binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP)]. Moreover, Trolox reduced oxidative stress by enhancing the expression of nuclear factor erythroid-related factor 2 (NRF2) and heme oxygenase 1 (HO1). Similarly, Trolox-induced synaptic markers, including synaptosomal associated protein 23 (SNAP23), synaptophysin (SYN), and post-synaptic density protein 95 (PSD-95), and memory functions in AD mice. Our findings could provide a useful and novel strategy for investigating new medications to treat AD-associated neurodegenerative diseases.

Multi-analyte proteomic analysis identifies blood-based neuroinflammation, cerebrovascular and synaptic biomarkers in preclinical Alzheimer's disease.

BACKGROUND: Blood-based biomarkers are gaining grounds for the detection of Alzheimer's disease (AD) and related disorders (ADRDs). However, two key obstacles remain: the lack of methods for multi-analyte assessments and the need for biomarkers for related pathophysiological processes like neuroinflammation, vascular, and synaptic dysfunction. A novel proteomic method for pre-selected analytes, based on proximity extension technology, was recently introduced. Referred to as the NULISAseq CNS disease panel, the assay simultaneously measures ~ 120 analytes related to neurodegenerative diseases, including those linked to both core (i.e., tau and amyloid-beta (Aß)) and non-core AD processes. This study aimed to evaluate the technical and clinical performance of this novel targeted proteomic panel. METHODS: The NULISAseq CNS disease panel was applied to 176 plasma samples from 113 individuals in the MYHAT-NI cohort of predominantly cognitively normal participants from an economically underserved region in southwestern Pennsylvania, USA. Classical AD biomarkers, including p-tau181, p-tau217, p-tau231, GFAP, NEFL, Aß40, and Aß42, were independently measured using Single Molecule Array (Simoa) and correlations and diagnostic performances compared. Aß pathology, tau pathology, and neurodegeneration (AT(N) statuses) were evaluated with [11C] PiB PET, [18F]AV-1451 PET, and an MRI-based AD-signature composite cortical thickness index, respectively. Linear mixed models were used to examine cross-sectional and Wilcoxon rank sum tests for longitudinal associations between NULISA and neuroimaging-determined AT(N) biomarkers. RESULTS: NULISA concurrently measured 116 plasma biomarkers with good technical performance (97.2 ± 13.9% targets gave signals above assay limits of detection), and significant correlation with Simoa assays for the classical biomarkers. Cross-sectionally, p-tau217 was the top hit to identify Aß pathology, with age, sex, and APOE genotype-adjusted AUC of 0.930 (95%CI: 0.878-0.983). Fourteen markers were significantly decreased in Aß-PET + participants, including TIMP3, BDNF, MDH1, and several cytokines. Longitudinally, FGF2, IL4, and IL9 exhibited Aß PET-dependent yearly increases in Aß-PET + participants. Novel plasma biomarkers with tau PET-dependent longitudinal changes included proteins associated with neuroinflammation, synaptic function, and cerebrovascular integrity, such as CHIT1, CHI3L1, NPTX1, PGF, PDGFRB, and VEGFA; all previously linked to AD but only reliable when measured in cerebrospinal fluid. The autophagosome cargo protein SQSTM1 exhibited significant association with neurodegeneration after adjusting age, sex, and APOE ε4 genotype. CONCLUSIONS: Together, our results demonstrate the feasibility and potential of immunoassay-based multiplexing to provide a comprehensive view of AD-associated proteomic changes, consistent with the recently revised biological and diagnostic framework. Further validation of the identified inflammation, synaptic, and vascular markers will be important for establishing disease state markers in asymptomatic AD.

Crucial role of Aquaporin-4 extended isoform in brain water Homeostasis and Amyloid-ß clearance: implications for Edema and neurodegenerative diseases.

The water channel aquaporin-4 (AQP4) is crucial for water balance in the mammalian brain. AQP4 has two main canonical isoforms, M23, which forms supramolecular structures called Orthogonal Arrays of Particles (OAP) and M1, which does not, along with two extended isoforms (M23ex and M1ex). This study examines these isoforms' roles, particularly AQP4ex, which influences water channel activity and localization at the blood-brain barrier. Using mice lacking both AQP4ex isoforms (AQP4ex-KO) and lacking both AQP4M23 isoforms (OAP-null) mice, we explored brain water dynamics under osmotic stress induced by an acute water intoxication (AWI) model. AQP4ex-KO mice had lower basal brain water content than WT and OAP-null mice. During AWI, brain water content increased rapidly in WT and AQP4ex-KO mice, but was delayed in OAP-null mice. AQP4ex-KO mice had the highest water content increase at 20 min. Immunoblot analysis showed stable total AQP4 in WT mice initially, with increases at 30 min. AQP4ex and its phosphorylated form (p-AQP4ex) levels rose quickly, but the p-AQP4ex/AQP4ex ratio dropped at 20 min. AQP4ex-KO mice showed a compensatory rise in canonical AQP4 at 20 min post-AWI. These findings highlight the important role of AQP4ex in water content dynamics in both normal and pathological states. To evaluate brain waste clearance, amyloid-ß (Aß) removal was assessed using a fluorescent Aß intra-parenchyma injection model. AQP4ex-KO mice demonstrated markedly impaired Aß clearance, with extended diffusion distances and reduced fluorescence in cervical lymph nodes, indicating inefficient drainage from the brain parenchyma. Mechanistically, the polarization of AQP4 at astrocytic endfeet is essential for efficient clearance flow, aiding interstitial fluid movement into the CSF and lymphatic system. In AQP4ex-KO mice, disrupted polarization forces reliance on slower, passive diffusion for solute clearance, significantly reducing Aß removal efficiency and altering extracellular space dynamics. Our results underscore the importance of AQP4ex in both brain water homeostasis and solute clearance, particularly Aß. These findings highlight AQP4ex as a potential therapeutic target for enhancing waste clearance mechanisms in the brain, which could have significant implications for treating brain edema and neurodegenerative diseases like Alzheimer's.

Cerebral Proteomic Changes in the rTg-D Rat Model of Cerebral Amyloid Angiopathy Type-2 With Cortical Microhemorrhages and Cognitive Impairments.

Cerebral amyloid angiopathy (CAA) is a common disorder of the elderly, a prominent comorbidity of Alzheimer's disease, and causes vascular cognitive impairment and dementia. Previously, we generated a novel transgenic rat model (rTg-D) that produces human familial CAA Dutch E22Q mutant amyloid ß-protein (Aß) in brain and develops arteriolar CAA type-2. Here, we show that deposition of fibrillar Aß promotes arteriolar smooth muscle cell loss and cerebral microhemorrhages that can be detected by magnetic resonance imaging and confirmed by histopathology. Aged rTg-D rats also present with cognitive deficits. Cerebral proteomic analyses revealed 241 proteins that were significantly elevated with an increase of >50% in rTg-D rats presenting with CAA compared to wild-type rats. Fewer proteins were significantly decreased in rTg-D rats. Of note, high temperature requirement peptidase A (HTRA1), a proteinase linked to transforming growth factor beta 1 (TGF-ß1) signaling, was elevated and found to accumulate in cerebral vessels harboring amyloid deposits. Pathway analysis indicated elevation of the TGF-ß1 pathway and increased TGF-ß1 levels were detected in rTg-D rats. In conclusion, the present findings provide new molecular insights into the pathogenesis of CAA and suggest a role for interactions between HTRA1 and TGF-ß1 in the disease process.

Cognition in (pre)symptomatic Dutch-type hereditary and sporadic cerebral amyloid angiopathy.

INTRODUCTION: Cerebral amyloid angiopathy (CAA) is a main cause of cognitive dysfunction in the elderly. We investigated specific cognitive profiles, cognitive function in the stage before intracerebral hemorrhage (ICH), and the association between magnetic resonance imaging (MRI) based cerebral small vessel disease (cSVD) burden in CAA because data on these topics are limited. METHODS: We included Dutch-type hereditary CAA (D-CAA) mutation carriers with and without ICH, patients with sporadic CAA (sCAA), and age-matched controls. Cognition was measured with a standardized test battery. Linear regression was performed to assess the association between MRI-cSVD burden and cognition. RESULTS: D-CAA ICH- mutation carriers exhibited poorer global cognition and executive function compared to age-matched controls. Patients with sCAA performed worse across all cognitive domains compared to D-CAA ICH+ mutation carriers and age-matched controls. MRI-cSVD burden is associated with decreased processing speed. DISCUSSION: CAA is associated with dysfunction in multiple cognitive domains, even before ICH, with increased MRI-cSVD burden being associated with slower processing speed. HIGHLIGHTS: Cognitive dysfunction is present in early disease stages of cerebral amyloid angiopathy (CAA) before the occurrence of symptomatic intracerebral hemorrhage (sICH). Presymptomatic Dutch-type CAA (D-CAA) mutation carriers show worse cognition than age-matched controls. More early awareness of cognitive dysfunction in CAA before first sICH is needed. Increased cerebral small vessel disease CAA-burden on magnetic resonance imaging is linked to a decrease in processing speed.

Engineered 3D human neurovascular model of Alzheimer's disease to study vascular dysfunction.

The blood-brain barrier (BBB) serves as a selective filter that prevents harmful substances from entering the healthy brain. Dysfunction of this barrier is implicated in several neurological diseases. In the context of Alzheimer's disease (AD), BBB breakdown plays a significant role in both the initiation and progression of the disease. This study introduces a three-dimensional (3D) self-assembled in vitro model of the human neurovascular unit to recapitulate some of the complex interactions between the BBB and AD pathologies. It incorporates primary human brain endothelial cells, pericytes and astrocytes, and stem cell-derived neurons and astrocytes harboring Familial AD (FAD) mutations. Over an extended co-culture period, the model demonstrates increased BBB permeability, dysregulation of key endothelial and pericyte markers, and morphological alterations mirroring AD pathologies. The model enables visualization of amyloid-beta (Aß) accumulation in both neuronal and vascular compartments. This model may serve as a versatile tool for neuroscience research and drug development to provide insights into the dynamic relationship between vascular dysfunction and AD pathogenesis.

Expressing miR-282 mitigates Aß42-induced neurodegeneration in Alzheimer's model in Drosophila.

Alzheimer's disease is a complex neurodegenerative condition characterized by the accumulation of amyloid beta plaques, leading to memory loss, cognitive decline, and impaired autonomous behavior. Despite extensive research, an effective treatment remains elusive. The buildup of amyloid beta plaques (Aß42) in the brain causes oxidative stress and disrupts normal molecular signaling, adversely affecting neuron function. Previous research has identified factors that can either exacerbate or mitigate neurodegenerative diseases. Our study aimed to uncover new factors involved in the pathogenesis of Alzheimer's disease. Using Drosophila as a model organism, we employed the Gal4/UAS system to express human Aß42 in the flies' retinal neurons which led to neurodegenerative changes in their compound eyes. To identify genetic modifiers, we conducted a screen by co-expressing microRNAs and found that miR-282 acts as a suppressor. Overexpressing miR-282 in the GMR > Aß42 background reduced Aß42-induced neurodegeneration. Further analysis using prediction tools and RNA interference experiments identified three potential downstream targets of miR-282: calpain-B, knot, and scabrous. Downregulating these genes via RNA interference in the GMR > Aß42 background mitigated neurodegeneration. Our research highlights miR-282 as a novel molecule that may influence the progression of Alzheimer's disease, offering potential avenues for future therapeutic or diagnostic developments.

Real-time analysis of the biomolecular interaction between gelsolin and Aß1-42 monomer and its implication for Alzheimer's disease.

Biomolecular interaction acts a pivotal part in understanding the mechanisms underlying the development of Alzheimer's disease (AD). Herein, we built a biosensing platform to explore the interaction between gelsolin (GSN) and different ß-amyloid protein 1-42 (Aß1-42) species, including Aß1-42 monomer (m-Aß), Aß1-42 oligomers with both low and high levels of aggregation (LLo-Aß and HLo-Aß) via dual polarization interferometry (DPI). Real-time molecular interaction process and kinetic analysis showed that m-Aß had the strongest affinity and specificity with GSN compared with LLo-Aß and HLo-Aß. The impact of GSN on inhibiting aggregation of Aß1-42 and solubilizing Aß1-42 aggregates was evaluated by circular dichroism (CD) spectroscopy. The maintenance of random coil structure of m-Aß and the reversal of ß-sheet structure in HLo-Aß were observed, demonstrating the beneficial effects of GSN on preventing Aß from aggregation. In addition, the structure of m-Aß/GSN complex was analyzed in detail by molecular dynamics (MD) simulation and molecular docking. The specific binding sites and crucial intermolecular forces were identified, which are believed to stabilize m-Aß in its soluble state and to inhibit the fibrilization of Aß1-42. Combined theoretical simulations and experiment results, we speculate that the success of GSN sequestration mechanism and the balance of GSN levels in cerebrospinal fluid and plasma of AD subjects may contribute to a delay in AD progression. This research not only unveils the molecular basis of the interaction between GSN and Aß1-42, but also provides clues to understanding the crucial functions of GSN in AD and drives the development of AD drugs and therapeutic approaches.