Amyloid Precursor Protein Research Articles

Loss of the APP regulator RHBDL4 preserves memory in an Alzheimer's disease mouse model.

Characteristic cerebral pathological changes of Alzheimer's disease (AD) such as glucose hypometabolism or the accumulation of cleavage products of the amyloid precursor protein (APP), known as Aβ peptides, lead to sustained endoplasmic reticulum (ER) stress and neurodegeneration. To preserve ER homeostasis, cells activate their unfolded protein response (UPR). The rhomboid-like-protease 4 (RHBDL4) is an enzyme that participates in the UPR by targeting proteins for proteasomal degradation. We demonstrated previously that RHBLD4 cleaves APP in HEK293T cells, leading to decreased total APP and Aβ. More recently, we showed that RHBDL4 processes APP in mouse primary mixed cortical cultures as well. Here, we aim to examine the physiological relevance of RHBDL4 in the brain. We first found that brain samples from AD patients and an AD mouse model (APPtg) showed increased RHBDL4 mRNA and protein expression. To determine the effects of RHBDL4's absence on APP physiology in vivo, we crossed APPtg mice to a RHBDL4 knockout (R4-/-) model. RHBDL4 deficiency in APPtg mice led to increased total cerebral APP and amyloidogenic processing when compared to APPtg controls. Contrary to expectations, as assessed by cognitive tests, RHBDL4 absence rescued cognition in 5-month-old female APPtg mice. Informed by unbiased RNAseq data, we demonstrated in vitro and in vivo that RHBDL4 absence leads to greater levels of active β-catenin due to decreased proteasomal clearance. Decreased β-catenin activity is known to underlie cognitive defects in APPtg mice and AD. Our work suggests that RHBDL4's increased expression in AD, in addition to regulating APP levels, leads to aberrant degradation of β-catenin, contributing to cognitive impairment.

Liposomal Formulations of Anti-Alzheimer Drugs and siRNA for Nose-to-Brain Delivery: Design, Safety and Efficacy In Vitro

β-site amyloid precursor protein cleaving enzyme (BACE1) represents a key target for Alzheimer’s disease (AD) therapy because it is essential for producing the toxic amyloid β (Aβ) peptide that plays a crucial role in the disease’s development. BACE1 inhibitors are a promising approach to reducing Aβ levels in the brain and preventing AD progression. However, systemic delivery of such inhibitors to the brain demonstrates limited efficacy because of the presence of the blood-brain barrier (BBB). Nose-to-brain (NtB) delivery has the potential to overcome this obstacle. Liposomal drug delivery systems offer several advantages over traditional methods for delivering drugs and nucleic acids from the nose to the brain. The current study aims to prepare, characterize, and evaluate in vitro liposomal forms of donepezil, memantine, BACE-1 siRNA, and their combination for possible treatment of AD via NtB delivery. All the liposomal formulations were prepared using the rotary evaporation method. Their cellular internalization, cytotoxicity, and the suppression of beta-amyloid plaque and other pro-inflammatory cytokine expressions were studied. The Calu-3 Transwell model was used as an in vitro system for mimicking the anatomical and physiological conditions of the nasal epithelium and studying the suitability of the proposed formulations for possible NtB delivery. The investigation results show that liposomes provided the effective intracellular delivery of therapeutics, the potential to overcome tight junctions in BBB, reduced beta-amyloid plaque accumulation and pro-inflammatory cytokine expression, supporting the therapeutic potential of our approach.Graphical

Specific Targeting and Imaging of RNA G-Quadruplex (rG4) Structure Using Non-G4-Containing l-RNA Aptamer and Fluorogenic l-Aptamer.

RNA G-quadruplex structures (rG4s) play important roles in the regulation of biological processes. So far, all the l-RNA aptamers developed to target rG4 of interest contain G4 motif itself, raising the question of whether non-G4-containing l-RNA aptamer can be developed to target rG4. Furthermore, it is unclear whether an l-Aptamer-based tool can be generated for G4 detection in vitro and imaging in cells. Herein, a new strategy is designed using a low GC content template library to develop a novel non-G4-containing l-RNA aptamer with strong binding affinity and improved binding specificity to rG4 of interest. The first non-G4-containing l-Aptamer, l-Apt.1-1, is identified with nanomolar binding affinity to amyloid precursor protein (APP) D-rG4. l-Apt.1-1 is applied to control APP gene expression in cells via targeting APP D-rG4 structure. Moreover, the first l-RNA-based fluorogenic bi-functional aptamer (FLAP) system is developed, and l-Apt.1-1_Pepper is engineered for in vitro detection and cellular imaging of APP D-rG4. This work provides an original approach for developing non-G4-containing l-RNA aptamer for rG4 targeting, and the novel l-Apt.1-1 developed for APP gene regulation, as well as the l-Apt.1-1_Pepper generated for imaging of APP rG4 structure can be further used in other applications in vitro and in cells.

Endo-Lysosomal Network Disorder Reprograms Energy Metabolism in SorL1-Null Rat Hippocampus.

Sortilin-related receptor 1 (SorL1) deficiency is a genetic predisposition to familial Alzheimer's disease (AD), but its pathology is poorly understood. In SorL1-null rats, a disorder of the global endosome-lysosome network (ELN) is found in hippocampal neurons. Deletion of amyloid precursor protein (APP) in SorL1-null rats could not completely rescue the neuronal abnormalities in the ELN of the hippocampus and the impairment of spatial memory in SorL1-null young rats. These in vivo observations indicated that APP is one of the cargoes of SorL1 in the regulation of the ELN, which affects hippocampal-dependent memory. When SorL1 is depleted, the endolysosome takes up more of the lysosome flux and damages lysosomal digestion, leading to pathological lysosomal storage and disturbance of cholesterol and iron homeostasis in the hippocampus. These disturbances disrupt the original homeostasis of the material-energy-subcellular structure and reprogram energy metabolism based on fatty acids in the SorL1-null hippocampus, instead of glucose. Although fatty acid oxidation increases ATP supply, it cannot reduce the levels of the harmful byproduct ROS during oxidative phosphorylation, as it does in glucose catabolism. Therefore, the SorL1-null rats exhibit hippocampal degeneration, and their spatial memory is impaired. Our research sheds light on the pathology of SorL1 deficiency in AD.

Thonningianin A from Penthorum chinense Pursh as a targeted inhibitor of Alzheimer's disease-related β-amyloid and Tau proteins.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by complex pathogenesis mechanisms. Among these, β-amyloid plaques and hyperphosphorylated Tau protein tangles have been identified as significant contributors to neuronal damage. This study investigates thonningianin A (TA) from Penthorum chinense Pursh (PCP) as a potential inhibitor targeting these pivotal proteins in AD progression. The inhibitory potential of PCP and TA on Aβ fibrillization was initially investigated. Subsequently, ultra-high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry and biolayer interferometry were employed to determine TA's affinity for both Aβ and Tau. The inhibitory effects of TA on the levels and cytotoxicity of AD-related proteins were then assessed. In 3xTg-AD mice, the therapeutic potential of TA was evaluated. Additionally, the molecular interactions between TA and either Aβ or Tau were explored using molecular docking. We found that PCP-total ethanol extract and TA significantly inhibited Aβ fibrillization. Additionally, TA demonstrated strong affinity to Aβ and Tau, reduced levels of amyloid precursor protein and Tau, and alleviated mitochondrial distress in PC-12 cells. In 3xTg-AD mice, TA improved cognition, reduced Aβ and Tau pathology, and strengthened neurons. Moreover, molecular analyses revealed efficient binding of TA to Aβ and Tau. In conclusion, TA, derived from PCP, shows significant neuroprotection against AD proteins, highlighting its potential as an anti-AD drug candidate.

BACE1 inhibitors: A promising therapeutic approach for the management of Alzheimer’s disease

Alzheimer’s disease is a neurological disorder marked by the accumulation of amyloid beta (Aβ) aggregates, resulting from mutations in the amyloid precursor protein. The enzyme β-secretase, also known as β-site amyloid precursor protein cleaving enzyme 1 (BACE1), plays a crucial role in generating Aβ peptides. With no targeted therapy available for Alzheimer’s disease, inhibiting BACE1 aspartic protease has emerged as a primary treatment target. Since 1999, compounds demonstrating potential binding to the BACE1 receptor have advanced to human trials. Structural optimization of synthetically derived compounds, coupled with computational approaches, has offered valuable insights for developing highly selective leads with drug-like properties. This review highlights pivotal studies on the design and development of BACE1 inhibitors as anti-Alzheimer’s disease agents. It summarizes computational methods employed in facilitating drug discovery for potential BACE1 inhibitors and provides an update on their clinical status, indicating future directions for novel BACE1 inhibitors. The promising clinical results of Elenbecestat (E-2609) catalyze the development of effective, selective BACE1 inhibitors in the future.

Abstract 01: Spatial Transcriptomics Reveals How Smooth Muscle Cells Transform to Renin-Expressing Cells During Homeostatic Challenge

Introduction: Juxtaglomerular (JG) cells sense changes in blood pressure through communication with neighboring cells, and/or the sympathetic nervous system upon which they release renin to maintain homeostasis. To meet the demands for circulating renin when homeostasis is threatened, smooth muscle cells (SMCs) of the renal arterioles are transformed to renin-synthesizing cells. Discriminating transformed cells versus JG cells using sorting and scRNA-seq is cumbersome, limiting our ability to explore the events underlying such transformation. Therefore, there is a need to study these cells in situ to assign and determine which epigenomic and cell communication pathways regulate renin expression and SMC transformation. Hypothesis: Transformation of SMCs to renin-expressing cells during homeostatic stress requires specific signals from neighboring cells in addition to intrinsic transcriptomic changes. Methods: A pilot study was performed using two three-month-old C57BL/6 mice fed either a normal diet, or a low-salt diet with the RAS inhibitor, captopril, to induce homeostatic stress. After one week, the kidneys were harvested and prepared for the 10X Genomics Visium platform. Sequencing results were preprocessed using the Space Ranger pipeline (v. 2.0.1) with the mouse mm10 genome prior to downstream analysis using the R packages Seurat, Signac, and CellChat. Results: Homeostatic challenge significantly increased Ren1 expression ( p Holm-adj. =4.63x10 -10 ) and led to more and stronger cellular interactions. Interstitial cells and JG cells contributed the largest percent increase in the observed signaling changes (6.5% and 4.5% respectively). Increased signals for collagen, amyloid precursor protein, osteopontin, laminin, thrombospondin 1, vascular endothelial growth factor, and growth arrest specific pathways drove changes between native and transformed renin-expressing cells. In addition to the established JG cell markers Ren1 and Akr1b7 , transformed cells had significantly increased expression ( p Bonferroni-adj < 0.01) of Hmgcs2 , Cyp4a14 , Suox , Acta2 , Slc2a5 , Ptp4a3 , Sncg , and Rad21 . Conclusions: In conclusion, spatial transcriptomics revealed the evolution of SMC transformation into renin phenotypes by uncovering pathways and genes understudied in the context of renin regulation. Future work will leverage higher resolution spatial technology and further explore the contribution of identified pathways to renin regulation and SMC transformation.

Natural Product Virtual-Interact-Phenotypic Target Characterization: A Novel Approach Demonstrated with Salvia Miltiorrhiza Extract

Natural products (NPs) have historically been a fundamental source for drug discovery. Yet the complex nature of NPs presents substantial challenges in pinpointing bioactive constituents, and corresponding targets. In the present study, an innovative Natural Product Virtual screening-Interaction-Phenotype (NP-VIP) strategy that integrates virtual screening, chemical proteomics, and metabolomics to identify and validate the bioactive targets of NPs. This approach reduces false positive results and enhances the efficiency of target identification. Salvia miltiorrhiza (SM), a herb with recognized therapeutic potential against ischemic stroke (IS), was used to illustrate the workflow. Utilizing virtual screening, chemical proteomics, and metabolomics, potential therapeutic targets for SM in the IS treatment were identified, totaling 29, 100, and 78, respectively. Further analysis via the NP-VIP strategy highlighted five high-confidence targets, including Poly [ADP-ribose] polymerase 1 (PARP1), signal transducer and activator of transcription 3 (STAT3), amyloid precursor protein (APP), glutamate-ammonia ligase (GLUL), and glutamate decarboxylase 67 (GAD67). These targets were subsequently validated and found to play critical roles in the neuroprotective effects of SM. The study not only underscores the importance of SM in treating IS but also sets a precedent for NP research, proposing a comprehensive approach that could be adapted for broader pharmacological explorations.

Phosphorylated Tau in the Taste Buds of Alzheimer's Disease Mouse Models.

Numerous systemic diseases manifest with oral symptoms and signs. The molecular diagnosis of Alzheimer's disease (AD), the most prevalent neurodegenerative disease worldwide, currently relies on invasive or expensive methods, emphasizing the imperative for easily accessible biomarkers. In this study, we explored the expression patterns of key proteins implicated in AD pathophysiology within the taste buds of mice. We detected the expression of amyloid precursor protein (APP) and tau protein in the taste buds of normal C57BL/6 mice. Phosphorylated tau was predominantly found in type II and III taste cells, while APP was located in type I taste cells. Remarkably, we observed significantly stronger immunoreactivity to phosphorylated tau in the taste buds of aged AD mouse models compared to age-matched controls. These findings underscore the oral expression of biomarkers associated with AD, highlighting the diagnostic potential of the oral cavity for neurodegenerative diseases.

Alzheimer-mutant γ-secretase complexes stall amyloid β-peptide production.

Missense mutations in the amyloid precursor protein (APP) and presenilin-1 (PSEN1) cause early-onset familial Alzheimer's disease (FAD) and alter proteolytic production of secreted 38-to-43-residue amyloid β-peptides (Aβ) by the PSEN1-containing γ-secretase complex, ostensibly supporting the amyloid hypothesis of pathogenesis. However, proteolysis of APP substrate by γ-secretase is processive, involving initial endoproteolysis to produce long Aβ peptides of 48 or 49 residues followed by carboxypeptidase trimming in mostly tripeptide increments. We recently reported evidence that FAD mutations in APP and PSEN1 cause deficiencies in early steps in processive proteolysis of APP substrate C99 and that this results from stalled γ-secretase enzyme-substrate and/or enzyme-intermediate complexes. These stalled complexes triggered synaptic degeneration in a C. elegans model of FAD independently of Aβ production. Here we conducted full quantitative analysis of all proteolytic events on APP substrate by γ-secretase with six additional PSEN1 FAD mutations and found that all six are deficient in multiple processing steps. However, only one of these (F386S) was deficient in certain trimming steps but not in endoproteolysis. Fluorescence lifetime imaging microscopy in intact cells revealed that all six PSEN1 FAD mutations lead to stalled γ-secretase enzyme-substrate/intermediate complexes. The F386S mutation, however, does so only in Aβ-rich regions of the cells, not in C99-rich regions, consistent with the deficiencies of this mutant enzyme only in trimming of Aβ intermediates. These findings provide further evidence that FAD mutations lead stalled and stabilized γ-secretase enzyme-substrate and/or enzyme-intermediate complexes and are consistent with the stalled process rather than the products of γ-secretase proteolysis as the pathogenic trigger.

Alzheimer’s disease: A CRISPR/CAS9-mediated therapeutic approach

The degenerative nature of Alzheimer's disease (AD) and its severe effects on cognitive function present a major challenge to worldwide healthcare systems. CRISPR/Cas9, one of the most recent developments in gene-editing technology, has created new opportunities to investigate possible AD treatment approaches. The present state of AD research is reviewed in this paper, along with the possibility of using CRISPR/Cas9-mediated methods to target important genetic elements involved in AD pathogenesis. Through targeted gene editing linked to tau protein malfunction, neuroinflammation, and amyloid-beta accumulation, CRISPR/Cas9 presents a viable approach to altering the molecular course of disease. Additionally, using CRISPR/Cas9 in patient-specific induced pluripotent stem cells (iPSCs) may lead to personalized medicine strategies for the treatment of AD. Issues like delivery strategies, off-target impacts, and moral dilemmas are also covered. All things considered, the application of CRISPR/Cas9 technology to AD research is a fresh and potentially revolutionary strategy for creating targeted treatments for this intricate neurodegenerative illness. For the purpose of treating AD, more preclinical and clinical research is necessary to confirm the security and effectiveness of CRISPR/Cas9-based therapies. With the use of the CRISPR/Cas9 system, precise and effective genome modification is possible, enabling targeted editing of particular genes linked to the pathophysiology of AD. Thanks to this technology, genetic mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) genes that are linked to family types of AD can be corrected. It is feasible to restore normal protein function and possibly lessen the pathogenic processes that underlie AD by fixing these mutations.

Biological function of Aβ peptides revealed by analysis of membrane-association properties: Implications for Azheimer's disease pathogenesis

Proteolytic processing of amyloid precursor protein (APP) plays a critical role in the pathogenesis of Azheimer's disease (AD). Sequential cleavage of APP by β and γ secretases leads to generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) peptides. Despite intense studies, the biological function of these peptides and the mechanism of Aβ42 toxicity is poorly understood. In the previous publications we proposed that association of Aβ peptides with the endosomal membranes may have important implications for pathogenesis of AD (Kim and Bezprozvanny, IJMS, 2021, vol 22, 13600; Kim and Bezprozvanny, IJMS, 2023, vol 24, 2092). To understand potential biological importance of such interaction, we focused on the region of Aβ peptides involved in peri-membrane association (E682 to N698). We discovered that association of this region with the membranes is reminiscent of several known anti-microbial peptides (AMP) such as PA13, Aurein1.2 and BP100. Our analysis further revealed that energy of peri-membrane association of Aβ40 is significantly weaker than for Aβ42 or AMP peptides, but it can be increased in the presence of non-amyloidogenic FAD mutations or in the presence of cholesterol in the membrane. Based on similarity with established mechanism of action of AMP peptides, we propose that Aβ peptides affect the curvature of endosomal membranes and shift the balance between endosomal recycling to plasma membrane and late endosomal/lysosomal pathway. We further propose that these effects are enhanced as a result of non-amyloidogenic FAD mutations in the sequence of Aβ peptides or in the presence of cholesterol in the membrane. The proposed model provides potential mechanistic explanation to synaptic defects induced by increased levels of Aβ42, by non-amyloidogenic FAD mutations in APP and by age-related increase in the levels of cholesterol in the brain.

Quercetin ameliorates neuroinflammatory and neurodegenerative biomarkers in the brain and improves neurobehavioral parameters in a repeated intranasal amyloid-beta exposed model of Alzheimer's disease.

Objectives: The aim of the present study was to study the potential therapeutic effects of quercetin in protection against repeated intranasal exposure of an amyloid-beta-induced mouse model. Methods: Mice received intranasal Aβ1-42 (5 μg/10 μL) exposure once daily for seven consecutive days. Quercetin was orally administered to them at 30 mg kg-1 and 100 mg kg-1 doses for one week starting from day five following Aβ1-42 peptide administration. Following this, the animals were evaluated for neurobehavioral parameters using a Morris water maze test and a novel object recognition test. Further to this, the biomarkers for neuroinflammation and neurodegeneration were evaluated in the hippocampus and cortex regions of the brain in these animals. Results: Multiple exposures to intranasal Aβ led to a significant decline in the learning and cognitive memory of the animals, whereas oral treatment with quercetin at dosages of 30 and 100 mg kg-1 alleviated Aβ-induced effects. Quercetin treatment significantly reduced Aβ accumulation, oxidative stress and proinflammatory cytokine biomarkers in the brain. In addition, it also alleviated the activation of astrocytic biomarkers, amyloid precursor protein and phosphorylated-tau proteins in the brain. Conclusion: Quercetin was found to be a potent antioxidant, anti-inflammatory compound with protection against neurodegenerative damage and improved learning and cognitive memory in a repeated Aβ-exposure model of AD.

Ovariectomy exacerbates the disturbance of excitation- inhibition balance in the brain of APP/PS-1/tau mice.

The prevalence of Alzheimer's disease (AD) is significantly gender-differentiated, with the number of female AD patients far exceeding that of males, accounting for two-thirds of the total prevalence. Although postmenopausal AD mice have been shown to have more prominent pathologic features and memory impairments than normal AD mice, the relevant molecular mechanisms leading to these outcomes have not been well elucidated. In the present study, we used the disturbance of excitation-inhibition balance in the postmenopausal brain as an entry point to explore the link between estrogen deficiency, disorders of the glutamatergic-GABAergic nervous system, and memory impairment. Wild-type (WT) mice and APP/PS1/tau (3 × Tg-AD) mice (10 months old) were randomly divided into four groups: WT+Sham group, WT+OVX group, 3 × Tg-AD+Sham group and 3 × Tg-AD+OVX group. Ovariectomy (OVX) was performed in the WT+OVX group and the 3 × Tg-AD+OVX group, and sham surgery was performed in the WT+Sham group and the 3 × Tg-AD+Sham group. The learning and memory ability and the anxiety and depression-like behavior changes of mice were evaluated by behavioral experiments, and the association between estrogen-estrogen receptors pathway and glutamatergic/GABAergic nervous system and female AD was evaluated by neurochemical experiments. In WT and 3 × Tg-AD mice, OVX resulted in impaired learning and memory abilities and anxiety and depression-like behaviors; reduced estrogen levels and downregulated the expression of estrogen receptors; upregulated the expression of amyloid-β, amyloid precursor protein, presenilin 1, and p-tau; upregulated the expression of Bcl-2-associated X protein and downregulated the expression of B-cell lymphoma-2, promoting cell apoptosis; reduced the number of neuronal dendrites and downregulated the expression of postsynaptic density protein-95; more importantly, OVX increased brain glutamate levels but downregulated the expression of N-methyl-D-aspartate receptor-2B, excitatory amino acid transporter 1, excitatory amino acid transporter 2, γ-aminobutyric acid receptor-A and γ-aminobutyric acid receptor-B. Our results suggested that OVX-induced estrogen-estrogen receptors pathway disruption caused learning and memory impairment and anxiety and depression-like behaviors, upregulated the expression of AD pathological markers, promoted apoptosis, destroyed neuronal structure, and most importantly, caused glutamatergic/GABAergic nervous system disorders.

Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APPSAA knock-in mouse model of Alzheimer's disease.

Reduced brain energy metabolism, mammalian target of rapamycin (mTOR) dysregulation, and extracellular amyloid beta (Aβ) oligomer (xcAβO) buildup are some well-known Alzheimer's disease (AD) features; how they promote neurodegeneration is poorly understood. We previously reported that xcAβOs inhibit nutrient-induced mitochondrial activity (NiMA) in cultured neurons. We now report NiMA disruption in vivo. Brain energy metabolism and oxygen consumption were recorded in heterozygous amyloid precursor protein knock-in (APPSAA) mice using two-photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy. NiMA is inhibited in APPSAA mice before other defects are detected in these Aβ-producing animals that do not overexpress APP or contain foreign DNA inserts into genomic DNA. Glycogen synthase kinase 3 (GSK3β) signals through mTORC1 to regulate NiMA independently of mitochondrial biogenesis. Inhibition of GSK3β with TWS119 stimulates NiMA in cultured human neurons, and mitochondrial activity and oxygen consumption in APPSAA mice. NiMA disruption in vivo occurs before plaques, neuroinflammation, and cognitive decline in APPSAA mice, and may represent an early stage in human AD. Amyloid beta blocks communication between lysosomes and mitochondria in vivo. Nutrient-induced mitochondrial activity (NiMA) is disrupted long before the appearance of Alzheimer's disease (AD) histopathology in heterozygous amyloid precursor protein knock-in (APPSAA/+) mice. NiMA is disrupted long before learning and memory deficits in APPSAA/+ mice. Pharmacological interventions can rescue AD-related NiMA disruption in vivo.

Long-Term Progression of a Residual Cerebral Amyloidoma: An Illustrative Case and Systematic Review

Cerebral amyloidomas (CA) are exceptionally rare tumor-like lesions composed of cerebral amyloid-beta, which is derived from the cleavage of the amyloid precursor protein. We presented a case of recurrent CA and performed a systematic review, comparing their initial presentation, imaging features, neurosurgical treatment, and natural history of the disease. A 65-year-old male with a history of right homonymous hemianopsia, who underwent subtotal resection of a CA 19 years before, presents to the emergency department with right hemiparesis, dysarthria, and a new onset of clonic seizures. Imaging revealed a left parieto-occipital lesion with calcifications and vasogenic edema. A gross-total resection was performed. Histopathology revealed a hypocellular eosinophilic lesion consistent with CA. Postoperatively, the patient recovered without new neurological deficits. One-year follow-up magnetic resonance imaging showed no residual or recurrence lesion. Eighty-seven cases, including ours, revealed that 65.5% (n= 57) were females with a median age of 54 years (IQR: 46-62). Most lesions were solitary (82.7%; 72 of 87 lesions). Frontal and parietal lobes were most commonly affected with 32.9% (n= 28) and 30.5% (n= 26), respectively. Seizures were the most common symptom followed by visual compromise. Calcifications were present in 19.5% (n= 17) of the lesions. This systematic review provides insights into the epidemiological, clinical, and neurosurgical characteristics, as well as the long-term prognosis of CA. This marks the first case in the reviewed literature with a 19-year period of follow-up where the patient had reoperation due to disease progression.

Exploring the Frontier: Antisense Long Non-Coding RNAs as Key Regulators in Alzheimer's Disease.

Alzheimer's Disease (AD) is the most prevalent, costly, and fatal neurodegenerative disorder of this century. Two hallmark features of AD are the anomalous cleavage of amyloid precursor protein (APP), which leads to the accumulation of amyloid-beta (Aβ), and the hyperphosphorylation of tau protein. Despite extensive research efforts, the pathology and pathogenesis of AD remain elusive. Recent investigations have highlighted the close association between antisense long non-coding RNAs (AS-lncRNAs) and various biological and functional aspects of AD. However, many AS-lncRNAs implicated in AD have not yet been comprehensively compiled and discussed. This paper reviews the role of AS-lncRNAs in neurodegenerative diseases, outlines their association with AD, and offers novel insights into the potential applications of antisense RNAs in the diagnosis and treatment of AD.

Exposure to Lead in Drinking Water Causes Cognitive Impairment via an Alzheimer's Disease Gene-Dependent Mechanism in Adult Mice.

Exposure to lead (Pb) is a major public health problem that could occur through contaminated soil, air, food, or water, either during the course of everyday life, or while working in hazardous occupations. Although Pb has long been known as a neurodevelopmental toxicant in children, a recent and growing body of epidemiological research indicates that cumulative, low-level Pb exposure likely drives age-related neurologic dysfunction in adults. Environmental Pb exposure in adulthood has been linked to risk of late-onset Alzheimer's disease (AD) and dementia. Although the biological mechanism underlying this link is unknown, it has been proposed that Pb exposure may increase the risk of AD via altering the expression of AD-related genes and, possibly, by activating the molecular pathways underlying AD-related pathology. We investigated Pb exposure using a line of genetically modified mice with AD-causing knock-in mutations in the amyloid precursor protein and presenilin 1 (APPΔNL/ΔNL x PS1P264L/P264L) that had been crossed with Leprdb/db mice to impart vulnerability to vascular pathology. Our data show that although Pb exposure in adult mice impairs cognitive function, this effect is not related to either an increase in amyloid pathology or to changes in the expression of common AD-related genes. Pb exposure also caused a significant increase in blood pressure, a well known effect of Pb. Interestingly, although the increase in blood pressure was unrelated to genotype, only mice that carried AD-related mutations developed cognitive dysfunction, in spite of showing no significant change in cerebrovascular pathology. These results raise the possibility that the increased risk of dementia associated with Pb exposure in adults may be tied to its subsequent interaction with either pre-existing or developing AD-related neuropathology.

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.

Iron chelation by oral deferoxamine treatment decreased brain iron and iron signaling proteins.

Deferoxamine (DFO) and other iron chelators are clinically used for cancer and stroke. They may also be useful for Alzheimers disease (AD) to diminish iron from microbleeds. DFO may also stimulate antioxidant membrane repair which is impaired during AD. DFO, and other chelators do enter the brain despite some contrary reports. Low dose, oral DFO was given in lab chow to wildtype (WT) C57BL/6 mice to evaluate potential impact on iron levels, iron-signaling and storage proteins, and amyloid precursor protein (APP) and processing enzymes. Young WT mice do not have microbleeds or disrupted blood-brain barrier of AD mice. Iron was measured by MRI and chemically after two weeks of dietary DFO. Cerebral cortex was examined for changes in iron metabolism, antioxidant signaling, and APP processing by Western blot. DFO decreased brain iron by 18% (MRI) and decreased seven major proteins that mediate iron metabolism by at least 25%. The iron storage proteins ferritin light and heavy chain decreased by at least 30%. APP and secretase enzymes also decreased by 30%. WT mice respond to DFO with decreased APP, amyloid processing enzymes, and antioxidant repair. Potential DFO treatment for early-stage AD by DFO should consider the benefits of lowered APP and secretase enzymes.