True or False? Alzheimer's disease is Type 3 Diabetes: Evidences from Bench to Bedside.

Globally, Alzheimer's disease (AD) is the most widespread chronic neurodegenerative disorder, leading to cognitive impairment, such as aphasia and agnosia, as well as mental symptoms, like behavioral abnormalities, that place a heavy psychological and financial burden on the families of the afflicted. Unfortunately, no particular medications exist to treat AD, as the current treatments only impede its progression.The link between AD and type 2 diabetes (T2D) has been increasingly revealed by research; the danger of developing both AD and T2D rises exponentially with age, with T2D being especially prone to AD. This has propelled researchers to investigate the mechanism(s) underlying this connection.A critical review of the relationship between insulin resistance, Aß, oxidative stress, mitochondrial hypothesis, abnormal phosphorylation of Tau protein, inflammatory response, high blood glucose levels, neurotransmitters and signaling pathways, vascular issues in AD and diabetes, and the similarities between the two diseases, is presented in this review. Grasping the essential mechanisms behind this detrimental interaction may offer chances to devise successful therapeutic strategies.

Alzheimer's disease and its treatment-yesterday, today, and tomorrow.

Alois Alzheimer described the first patient with Alzheimer's disease (AD) in 1907 and today AD is the most frequently diagnosed of dementias. AD is a multi-factorial neurodegenerative disorder with familial, life style and comorbidity influences impacting a global population of more than 47 million with a projected escalation by 2050 to exceed 130 million. In the USA the AD demographic encompasses approximately six million individuals, expected to increase to surpass 13 million by 2050, and the antecedent phase of AD, recognized as mild cognitive impairment (MCI), involves nearly 12 million individuals. The economic outlay for the management of AD and AD-related cognitive decline is estimated at approximately 355 billion USD. In addition, the intensifying prevalence of AD cases in countries with modest to intermediate income countries further enhances the urgency for more therapeutically and cost-effective treatments and for improving the quality of life for patients and their families. This narrative review evaluates the pathophysiological basis of AD with an initial focus on the therapeutic efficacy and limitations of the existing drugs that provide symptomatic relief: acetylcholinesterase inhibitors (AChEI) donepezil, galantamine, rivastigmine, and the N-methyl-D-aspartate receptor (NMDA) receptor allosteric modulator, memantine. The hypothesis that amyloid-ß (Aß) and tau are appropriate targets for drugs and have the potential to halt the progress of AD is critically analyzed with a particular focus on clinical trial data with anti-Aß monoclonal antibodies (MABs), namely, aducanumab, lecanemab and donanemab. This review challenges the dogma that targeting Aß will benefit the majority of subjects with AD that the anti-Aß MABs are unlikely to be the "magic bullet". A comparison of the benefits and disadvantages of the different classes of drugs forms the basis for determining new directions for research and alternative drug targets that are undergoing pre-clinical and clinical assessments. In addition, we discuss and stress the importance of the treatment of the co-morbidities, including hypertension, diabetes, obesity and depression that are known to increase the risk of developing AD.

Role of curcumin on beta-amyloid protein, tau protein, and biochemical and oxidative changes in streptozotocin-induced diabetic rats.

Diabetes is one of the most common endocrine metabolic diseases and is associated with the accumulation of beta-amyloid plaques in the brain. Amyloid beta (Aß) and abnormal tau proteins are effective in the development of Alzheimer's disease. The aim of this study is to investigate the therapeutic and protective effects of curcumin on beta-amyloid (Aß) accumulation and tau protein expression levels, as well as biochemical and oxidative changes in streptozotocin-induced diabetes in rats. The study comprised five groups, each consisting of eight rats: control, diabetic, curcumin, curcumin during diabetic induction, and curcumin post-diabetic induction. Groups 2 and 4 were administered a single dose of 45 mg/kg streptozotocin on day 1, while group 5 received it on day 28. Curcumin was orally administered via gavage at a dose of 100 mg/kg/day for 35 days to the third, fourth, and fifth groups. At the end of the trial (day 35), blood sugar levels and insulin resistance were similar between the control and curcumin-treated groups but significantly higher in the diabetic groups (P < 0.05). The protective effect of curcumin is tested during induction and active diabetes. The results indicated that diabetic rats displayed increased levels of Aß, tau protein, and total oxidant capacity (TOS) compared to the curcumin-treated groups. Additionally, the total antioxidant capacity (TAS) levels were lower in the diabetic rats (P < 0.05). Aß protein levels are lower in both the serum and brain of rats with active diabetes and treated with curcumin compared to control rats (P > 0.05). In addition, serum TAS levels were higher in rats treated with curcumin following the induction of diabetes than pre-induction of diabetes (P > 0.05). The TOS levels in the serum were higher in the rats treated with curcumin during active diabetes compared to the rats treated prior to the induction of diabetes (P < 0.05). However, no significant difference was observed in the brain. The above results show that curcumin has an effect on reducing oxidative stress caused by diabetes and increasing antioxidant activity.

Serum albumin-embedding copper nanoclusters inhibit Alzheimer's ß-amyloid fibrillogenesis and neuroinflammation.

Increasing evidence suggests that the accumulations of reactive oxygen species (ROS), ß-amyloid (Aß), and neuroinflammation are crucial pathological hallmarks for the onset of Alzheimer's disease (AD), yet there are few effective treatment strategies. Therefore, design of nanomaterials capable of simultaneously elimination of ROS and inhibition of Aß aggregation and neuroinflammation is urgently needed for AD treatment. Herein, we designed human serum albumin (HSA)-embedded ultrasmall copper nanoclusters (CuNCs@HSA) via an HSA-mediated fabrication strategy. The as-prepared CuNCs@HSA exhibited outstanding multiple enzyme-like properties, including superoxide dismutase (>5000 U/mg), catalase, and glutathione peroxidase activities as well as hydroxyl radicals scavenging ability. Besides, CuNCs@HSA prominently inhibited Aß fibrillization, and its inhibitory potency was 2.5-fold higher than native HSA. Moreover, CuNCs@HSA could significantly increase the viability of Aß-treated cells from 60 % to over 96 % at 40 µg/mL and mitigate Aß-induced oxidative stresses. The secretion of neuroinflammatory cytokines by lipopolysaccharide-induced BV-2 cells, including tumor necrosis factor-α and interleukin-6, was alleviated by CuNCs@HSA. In vivo studies manifested that CuNCs@HSA effectively suppressed the formation of plaques in transgenic C. elegans, reduced ROS levels, and extended C. elegans lifespan by 5 d. This work, using HSA as a template to mediate the fabrication of copper nanoclusters with robust ROS scavenging capability, exhibited promising potentials in inhibiting Aß aggregation and neuroinflammation for AD treatment.

Mechanistic Insights Behind the Self-Assembly of Human Insulin under the Influence of Surface-Engineered Gold Nanoparticles.

Elucidating the underlying principles of amyloid protein self-assembly at nanobio interfaces is extremely challenging due to the diversity in physicochemical properties of nanomaterials and their physical interactions with biological systems. It is, therefore, important to develop nanoscale materials with dynamic features and heterogeneities. In this work, through engineering of hierarchical polyethylene glycol (PEG) structures on gold nanoparticle (GNP) surfaces, tailored nanomaterials with different surface properties and conformations (GNPs-PEG) are created for modulating the self-assembly of a widely studied protein, insulin, under amyloidogenic conditions. Important biophysical studies including thioflavin T (ThT) binding, circular dichroism (CD), surface plasmon resonance (SPR), and atomic force microscopy (AFM) showed that higher-molecular weight GNPs-PEG triggered the formation of amyloid fibrils by promoting adsorption of proteins at nanoparticle surfaces and favoring primary nucleation rate. Moreover, the modulation of fibrillation kinetics reduces the overall toxicity of insulin oligomers and fibrils. In addition, the interaction between the PEG polymer and amyloidogenic insulin examined using MD simulations revealed major changes in the secondary structural elements of the B chain of insulin. The experimental findings provide molecular-level descriptions of how the PEGylated nanoparticle surface modulates protein adsorption and drives the self-assembly of insulin. This facile approach provides a new avenue for systematically altering the binding affinities on nanoscale surfaces by tailoring their topologies for examining adsorption-induced fibrillogenesis phenomena of amyloid proteins. Together, this study suggests the role of nanobio interfaces during surface-induced heterogeneous nucleation as a primary target for designing therapeutic interventions for amyloid-related neurodegenerative disorders.

Red emissive fluorescent carbon dots based on ternary carbon source for imaging α-synuclein fibrils.

The misfolding and aggregation of α-synuclein monomers usually cause the occurrence and development of Parkinson's disease (PD). It is important to develop effective methods for detection of α-synuclein aggregates. Carbon dots (CDs) could be the potential fluorescence probe for this purpose owing to their appreciated optical properties. However, undefined structure of CDs and complicated three-dimensional structure of protein severely hindered the design of fluorescence probe towards protein aggregates. Herein, a red emissive fluorescent amphiphilic CD, named as CL-9, was designed with a high sensitivity to α-synuclein fibrils by a one-step heating process, using the ternary carbon source, including Congo red, l-tryptophan and urea. The CL-9 exhibited turn-on red emissive fluorescence towards α-synuclein fibril, but remained no change towards its monomer. Compared with the original Congo red dye, CL-9 exhibited stronger turn-on red fluorescence towards α-synuclein fibrils with better anti-photobleaching resistance, biocompatibility and signal-to-noise ratio. The CL-9 was successful as a fluorescent probe to image α-synuclein fibrils in NL-5901 C. elegans. The present study provided a feasible approach using the multiple carbon sources to construct the CDs based fluorescence probe targeting amyloid proteins.

Association Between Clonal Hematopoiesis of Indeterminate Potential and Brain ß-Amyloid Deposition in Korean Patients With Cognitive Impairment.

Few studies have focused on the association between clonal hematopoiesis of indeterminate potential (CHIP) and ß-amyloid (Aß) deposition in the brain, which causes Alzheimer's disease. We aimed to investigate the potential role of CHIP in brain Aß deposition in Korean patients. We enrolled 58 Korean patients over 50 yrs of age with cognitive impairment who underwent brain Aß positron emission tomography. We explored CHIP in their peripheral blood using deep-targeted next-generation sequencing. Irrespective of the presence or absence of brain Aß deposition, mutations in DNMT3A and the C:G>T:A single-nucleotide variants were identified as the primary characteristics, which reflect aged hematopoiesis in the study population. Multivariate logistic regression revealed that the presence of CHIP was not associated with brain Aß deposition. As both CHIP and brain Aß deposition are associated with aging, further research is required to elucidate their possible interplay.

Research on the pathogenesis of Alzheimer's disease based on thalamocortical computational model.

Alpha rhythm slowing is an important electroencephalogram(EEG) feature associated with (AD). This study aims to understand the correlation between alpha band deceleration and molecular changes from the perspective of neural computing. Considering the effect of Aß amyloid deposition on the inhibitory changes in the thalamic, a thalamic cortical model coupled with Aß amyloid is established. The results show that Aß amyloid deposition may induce neurotoxicity in thalamic reticular nucleus neurons, which results in inhibitory changes in the thalamus and slows the alpha rhythm of EEG output from the thalamus. In order to understand the pathogenesis more intuitively, some numerical simulations are provided to illustrate the obtained theories. This research is helpful to understand the pathogenesis of AD, so as to provide theoretical basis for the intervention and control of the disease.

Prominent tauopathy and intracellular ß-amyloid accumulation triggered by genetic deletion of cathepsin D: implications for Alzheimer disease pathogenesis.

BACKGROUND: Cathepsin D (CatD) is a lysosomal protease that degrades both the amyloid-ß protein (Aß) and the microtubule-associated protein, tau, which accumulate pathognomonically in Alzheimer disease (AD), but few studies have examined the role of CatD in the development of Aß pathology and tauopathy in vivo. METHODS: CatD knockout (KO) mice were crossed to human amyloid precursor protein (hAPP) transgenic mice, and amyloid burden was quantified by ELISA and immunohistochemistry (IHC). Tauopathy in CatD-KO mice, as initially suggested by Gallyas silver staining, was further characterized by extensive IHC and biochemical analyses. Controls included human tau transgenic mice (JNPL3) and another mouse model of a disease (Krabbe A) characterized by pronounced lysosomal dysfunction. Additional experiments examined the effects of CatD inhibition on tau catabolism in vitro and in cultured neuroblastoma cells with inducible expression of human tau. RESULTS: Deletion of CatD in hAPP transgenic mice triggers large increases in cerebral Aß, manifesting as intense, exclusively intracellular aggregates; extracellular Aß deposition, by contrast, is neither triggered by CatD deletion, nor affected in older, haploinsufficient mice. Unexpectedly, CatD-KO mice were found to develop prominent tauopathy by just ∼ 3 weeks of age, accumulating sarkosyl-insoluble, hyperphosphorylated tau exceeding the pathology present in aged JNPL3 mice. CatD-KO mice exhibit pronounced perinuclear Gallyas silver staining reminiscent of mature neurofibrillary tangles in human AD, together with widespread phospho-tau immunoreactivity. Striking increases in sarkosyl-insoluble phospho-tau (∼ 1250%) are present in CatD-KO mice but notably absent from Krabbe A mice collected at an identical antemortem interval. In vitro and in cultured cells, we show that tau catabolism is slowed by blockade of CatD proteolytic activity, including via competitive inhibition by Aß42. CONCLUSIONS: Our findings support a major role for CatD in the proteostasis of both Aß and tau in vivo. To our knowledge, the CatD-KO mouse line is the only model to develop detectable Aß accumulation and profound tauopathy in the absence of overexpression of hAPP or human tau with disease-associated mutations. Given that tauopathy emerges from disruption of CatD, which can itself be potently inhibited by Aß42, our findings suggest that impaired CatD activity may represent a key mechanism linking amyloid accumulation and tauopathy in AD.

Selective Orexin 2 Receptor Blockade Alleviates Cognitive Impairments and the Pathological Progression of Alzheimer's Disease in 3xTg-AD Mice.

The orexin system is closely related to the pathogenesis of Alzheimer's disease (AD). Orexin-A aggravates cognitive dysfunction and increases amyloid ß (Aß) deposition in AD model mice, but studies of different dual orexin receptor (OXR) antagonists in AD have shown inconsistent results. Our previous study revealed that OX1R blockade aggravates cognitive deficits and pathological progression in 3xTg-AD mice, but the effects of OX2R and its potential mechanism in AD have not been reported. In the present study, OX2R was blocked by oral administration of the selective OX2R antagonist MK-1064, and the effects of OX2R blockade on cognitive dysfunction and neuropsychiatric symptoms in 3xTg-AD mice were evaluated via behavioral tests. Then, immunohistochemistry, western blotting, and ELISA were used to detect Aß deposition, tau phosphorylation, and neuroinflammation, and electrophysiological and wheel-running activity recording were recorded to observe hippocampal synaptic plasticity and circadian rhythm. The results showed that OX2R blockade ameliorated cognitive dysfunction, improved LTP depression, increased the expression of PSD-95, alleviated anxiety- and depression-like behaviors and circadian rhythm disturbances in 3xTg-AD mice, and reduced Aß pathology, tau phosphorylation, and neuroinflammation in the brains of 3xTg-AD mice. These results indicated that chronic OX2R blockade exerts neuroprotective effects in 3xTg-AD mice by reducing AD pathology at least partly through improving circadian rhythm disturbance and the sleep-wake cycle and that OX2R might be a potential target for the prevention and treatment of AD; however, the potential mechanism by which OX2R exerts neuroprotective effects on AD needs to be further investigated.

Role of Amyloidogenic and Non-Amyloidogenic Protein Spaces in Neurodegenerative Diseases and their Mitigation Using Theranostic Agents.

Neurodegenerative diseases (NDDs) refer to a complex heterogeneous group of diseases which are associated with the accumulation of amyloid fibrils or plaques in the brain leading to progressive loss of neuronal functions. Alzheimer's disease is one of the major NDD responsible for 60-80 % of all dementia cases. Currently, there are no curative or disease-reversing/modifying molecules for many of the NDDs except a few such as donepezil, rivastigmine, galantamine, carbidopa and levodopa which treat the disease-associated symptoms. Similarly, there are very few FDA-approved tracers such as flortaucipir (Tauvid) for tau fibril imaging and florbetaben (Neuraceq), flutemetamol (Vizamyl), and florbetapir (Amyvid) for amyloid imaging available for diagnosis. Recent advances in the cryogenic electron microscopy reported distinctly different microstructures for tau fibrils associated with different tauopathies highlighting the possibility to develop tauopathy-specific imaging agents and therapeutics. In addition, it is important to identify the proteins that are associated with disease development and progression to know about their 3D structure to develop various diagnostics, therapeutics and theranostic agents. The current article discusses in detail the disease-associated amyloid and non-amyloid proteins along with their structural insights. We comprehensively discussed various novel proteins associated with NDDs and their implications in disease pathology. In addition, we document various emerging chemical compounds developed for diagnosis and therapy of different NDDs with special emphasis on theranostic agents for better management of NDDs.

Thermodynamics of oligomerization and Helix-to-sheet structural transition of amyloid ß-protein on anionic phospholipid vesicles.

Understanding oligomerization and aggregation of the amyloid-ß protein is important to elucidate the pathological mechanisms of Alzheimer's disease, and lipid membranes play critical roles in this process. In addition to studies reported by other groups, our group has also reported that the negatively-charged lipid bilayers with a high positive curvature induced α-helix-to-ß-sheet conformational transitions of amyloid-ß-(1-40) upon increase in protein density on the membrane surface and promoted amyloid fibril formation of the protein. Herein, we investigated detailed mechanisms of the conformational transition and oligomer formation of the amyloid-ß protein on the membrane surface. Changes in the fractions of the three protein conformers (free monomer, membrane-bound α-helix-rich conformation, and ß-sheet-rich conformation) were determined from the fluorescent spectral changes of the tryptophan probe in the protein. The helix-to-sheet structural transition on the surface was described by a thermodynamic model of octamer formation driven by entropic forces including hydrophobic interactions. These findings provide useful information for understanding the self-assembly of amyloidogenic proteins on lipid membrane surfaces.

Dynamic prediction of goal location by coordinated representation of prefrontal-hippocampal theta sequences.

Prefrontal (PFC) and hippocampal (HPC) sequences of neuronal firing modulated by theta rhythms could represent upcoming choices during spatial memory-guided decision-making. How the PFC-HPC network dynamically coordinates theta sequences to predict specific goal locations and how it is interrupted in memory impairments induced by amyloid beta (Aß) remain unclear. Here, we detected theta sequences of firing activities of PFC neurons and HPC place cells during goal-directed spatial memory tasks. We found that PFC ensembles exhibited predictive representation of the specific goal location since the starting phase of memory retrieval, earlier than the hippocampus. High predictive accuracy of PFC theta sequences existed during successful memory retrieval and positively correlated with memory performance. Coordinated PFC-HPC sequences showed PFC-dominant prediction of goal locations during successful memory retrieval. Furthermore, we found that theta sequences of both regions still existed under Aß accumulation, whereas their predictive representation of goal locations was weakened with disrupted spatial representation of HPC place cells and PFC neurons. These findings highlight the essential role of coordinated PFC-HPC sequences in successful memory retrieval of a precise goal location.

Quercetin-derived red emission carbon dots: A multifunctional theranostic nano-agent against Alzheimer's ß-amyloid fibrillogenesis.

Multifunctional agents with therapeutic and diagnostic capabilities are imperative to the prevention of Alzheimer's disease (AD), which is considered due to abnormal aggregation and deposition of ß-amyloid protein (Aß) as well as oxidative stress. Herein, quercetin (Que)- and p-phenylenediamine (p-PD)-derived red emission carbon dots (CDs) synthesized via a one-step hydrothermal method were designed as a novel theranostic nano-agent for the multi-target treatment of AD. R-CD-75 with an optimized composition exhibited significant inhibition of Aß aggregation and rapid depolymerization of mature Aß fibrils (<4 h) at micromolar concentrations (2 and 5 µg/mL, respectively). Moreover, R-CD-75 potently scavenged reactive oxygen species and showed turned-on red fluorescence imaging of Aß plaques both in vitro and in vivo. In vitro assays proved that R-CD-75 significantly mitigated the Aß-induced cytotoxicity and enhanced the cultured cell viability from 74.9 % to 98.0 %, while in vivo studies demonstrated that R-CD-75 prolonged the lifespan of AD nematodes by over 50 % (from 13 to 20 d). Compared to the precursors Que and p-PD, R-CD-75 inherited some of their structures and functional groups, such as aromatic structures, phenolic hydroxyl and amino groups, which were considered to interact with Aß species through hydrogen bonding, electrostatic interactions, hydrophobic interactions, and π-π stacking, thus contributing to its effectiveness in its theranostic functions. This research has opened a new avenue to the development of potent theranostic agents by designing novel carbon dots.

Effects of pressing moxibustion at Baihui (GV 20) and Guanyuan (CV 4) on cognitive impairment and serum levels of Aß1-42, tau, P-tau in patients with mild to moderate Alzheimer's disease. / åŽ‹ç¸ç™¾ä¼šã€å ³å ƒå¯¹è½»ä¸­åº¦é˜¿å°”èŒ¨æµ·é»˜ç— æ‚£è€ è®¤çŸ¥éšœç¢åŠè¡€æ¸ Aß1-42、tau、P-tau水平的影响.

OBJECTIVES: To compare the effects of pressing moxibustion at Baihui (GV 20) and Guanyuan (CV 4) combined with donepezil hydrochloride tablets and donepezil hydrochloride tablets alone on cognitive impairment in patients with mild to moderate Alzheimer's disease(AD), and to explore the mechanism of pressing moxibustion in the treatment of mild to moderate AD from the serum levels of ß-amyloid 1-42 (Aß1-42), microtubule-associated protein tau and phosphorylated tau (P-tau). METHODS: A total of 76 patients with mild to moderate AD were randomly divided into an observation group (38 cases, 4 cases dropped out) and a control group (38 cases, 2 cases dropped out). Patients in the control group were given oral donepezil hydrochloride tablets (5 mg each time, once a day). On the basis of the control group, patients in the observation group were treated with pressing moxibustion at Baihui (GV 20) and Guanyuan (CV 4), 5 cones per acupoint, once every other day, three times a week. Both groups were treated for 8 weeks. The scores of mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA) were compared between the two groups before treatment, after treatment and after 4 and 12 weeks of treatment completion. The serum levels of Aß1-42, tau and P-tau were detected before and after treatment in the two groups, and the safety was evaluated. RESULTS: At each time point after treatment, the MMSE and MoCA scores of the two groups were higher than those before treatment (P<0.05), and the scores in the observation group were higher than those in the control group (P<0.05). After treatment, the serum levels of Aß1-42, tau and P-tau in the two groups were lower than those before treatment (P<0.05), and above indexes in the observation group were lower than those in the control group (P<0.05). There was no significant difference in the safety level between the two groups (P>0.05). CONCLUSIONS: The short-term and long-term effect of pressing moxibustion at Baihui (GV 20) and Guanyuan (CV 4) combined with donepezil hydrochloride tablets in improving cognitive impairment in mild to moderate AD is better than that of donepezil hydrochloride tablets alone, and can reduce serum levels of Aß1-42, tau and P-tau, which may be one of the mechanisms of pressing moxibustion to improve cognitive impairment.

The Association of Alzheimer's Disease-Related Blood-Based Biomarkers with Cognitive Screening Test Performance in the Congolese Population in Kinshasa.

BACKGROUND: Alzheimer's disease (AD), the most common cause of dementia, poses a significant global burden. Diagnosis typically involves invasive and costly methods like neuroimaging or cerebrospinal fluid (CSF) biomarker testing of phosphorylated tau (p-tau) and amyloid-ß42/40 (Aß42/40). Such procedures are especially impractical in resource-constrained regions, such as the Democratic Republic of Congo (DRC). Blood-based biomarker testing may provide a more accessible screening opportunity. OBJECTIVE: This study aims to examine if AD-related blood-based biomarkers are associated with cognitive test performance in the Congolese population, where limited research has been conducted. METHODS: In this cross-sectional study of 81 Congolese individuals, cognitive assessments (Alzheimer's Questionnaire (AQ) and Community Screening Interview for Dementia (CSID)) distinguished dementia cases from controls. Blood draws were taken to assess p-tau 181 and Aß42/40 biomarkers. Relationships between the biomarkers and cognitive performance were analyzed using multiple linear regression models. RESULTS: Lower plasma Aß42/40 was significantly associated with lower CSID scores and higher AQ scores, indicative of AD (p < 0.001). These relationships were observed in healthy controls (CSID p = 0.01, AQ p = 0.03), but not in dementia cases. However, p-tau 181 did not exhibit significant associations with either measure. Factors such as age, sex, education, presence of APOEɛ4 allele, did not alter these relationships. CONCLUSIONS: Understanding relationships between AD-related screening tests and blood biomarkers is a step towards utilization of blood-based biomarker tests as a screening tool for AD, especially in resource-limited regions. Further research should be conducted to evaluate blood biomarker test efficacy in larger samples and other populations.

Unravelling the in vitro and in vivo potential of selenium nanoparticles in Alzheimer's disease: A bioanalytical review.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive cognitive decline and the accumulation of beta-amyloid plaques and tau tangles in the brain. Current therapies have limited efficacy, prompting the search for novel treatments. Selenium nanoparticles (SeNPs) have emerged as promising candidates for AD therapy due to their unique physicochemical properties and potential therapeutic effects. This review provides an overview of SeNPs and their potential application in AD treatment, as well as the main bioanalytical techniques applied in this field. SeNPs possess antioxidant and anti-inflammatory properties, making them potential candidates to combat the oxidative stress and neuroinflammation associated with AD. Moreover, SeNPs have shown the ability to cross the blood-brain barrier (BBB), allowing them to target brain regions affected by AD pathology. Various methods for synthesizing SeNPs are explored, including chemical, physical and biological synthesis approaches. Based on the employment of algae, yeast, fungi, and plants, green methods offer a promising and biocompatible alternative for SeNPs production. In vitro studies have demonstrated the potential of SeNPs in reducing beta-amyloid aggregation and inhibiting tau hyperphosphorylation, providing evidence of their neuroprotective effects on neuronal cells. In vivo studies using transgenic mouse models and AD-induced symptoms have shown promising results, with SeNPs treatment leading to cognitive improvements and reduced amyloid plaque burden in the hippocampus. Looking ahead, future trends in SeNPs research involve developing innovative brain delivery strategies to enhance their therapeutic potential, exploring alternative animal models to complement traditional mouse studies, and investigating multi-targeted SeNPs formulations to address multiple aspects of AD pathology. Overall, SeNPs represent a promising avenue for AD treatment, and further research in this field may pave the way for effective and much-needed therapeutic interventions for individuals affected by this debilitating disease.

Macrophage Membrane-Modified MoS2 Quantum Dots as a Nanodrug for Combined Multi-Targeting of Alzheimer's Disease.

The complex pathological mechanism of Alzheimer's disease (AD) limits the efficacy of simple drug therapy, and drugs are difficult to penetrate the blood-brain barrier (BBB). Therefore, it is a breakthrough to enhance the therapeutic effect of AD by rationally using multiple therapeutic strategies to inhibit multiple pathological targets. In this study, macrophage membrane (MM) with active targeting inflammation function is used to functionalize molybdenum disulfide quantum dots (MoS2 QDs) with the properties of elimination of reactive oxygen species (ROS) and anti-Aß1-42 deposition to form the nano drug (MoS2 QDs/MM), and play the role of multi-target combined therapy with NIR. The results show that MoS2 QDs/MM has a targeted therapeutic effect on ROS elimination and anti-deposition of Aß1-42 . In addition, the combined therapy group effectively reduced Aß1-42 mediated cytotoxicity. The modification of MM could effectively target the brain, and NIR irradiation could actively increase the cross of BBB of materials. In vivo behavioral study also show that APP/PS1 mice in the combined treatment group showed the similar exploration desire and learning ability to mice in the group of WT. MoS2 QDs/MM is an excellent nano drug with multiple effects, which has advantages in the field of neurological diseases with crisscross pathogenesis.

Amiloidose renal familiar em cães da raça Shar-Pei / Family renal amyloidosis in Shar-Pei dogs / Amiloidosis renal familiar en perros Shar-Pei

A amiloidose renal familiar é uma doença incomum em cães, que afeta os rins e está associada ao acúmulo anormal de proteínas amiloides, com capacidade de promover danos orgânicos progressivos com comprometimento de funcionalidade. Caracterizada pela presença de conteúdo proteináceo glomerular, a amiloidose frequentemente está associada a quadros de falência renal, com presença de sinais clínicos variados, sendo uma condição grave e complexa. O presente artigo tem como objetivo descrever os achados clínico-laboratoriais, de imagem e histopatológicos de amiloidose familiar em dois cães da raça Shar-pei. Os animais apresentavam parentesco direto e evidenciavam sinais de cansaço, prostração e emagrecimento progressivo. As evidências clínico-laboratoriais e ultrassonográficas sugeriram a presença de glomerulonefropatia, sendo essa confirmada por exame histopatológico. Os dois cães, diante da gravidade do quadro, foram a óbito. A análise histopatológica evidenciou deposição de material proteináceo fibrilar na região glomerular e tubular, bem como infiltrado linfoplasmocítico, característicos de amiloidose renal. É essencial lembrar que a amiloidose renal familiar em cães é uma doença complexa e que as origens devem ser investigadas. O tratamento é desafiador, diante da inexistência de um manejo terapêutico definido para a doença, sendo este muitas vezes ineficaz. A empatia e o cuidado no manejo dessa condição podem ajudar a melhorar a qualidade de vida do paciente e fornecer conforto ao proprietário durante esse processo desafiador.

Family renal amyloidosis is an uncommon disease in dogs, which affects the kidneys and is associated with abnormal accumulation of amyloid proteins, capable of promoting progressive organic damage with impairment of functionality. Characterized by the presence of glomerular proteinaceous content, amyloidosis is often associated with renal failure, with the presence of varied clinical signs, being a serious and complex condition. This article aims to describe the clinical, laboratory, imaging and histopathological findings of familial amyloidosis in two Shar-pei dogs. The animals were directly related and evidenced signs of tiredness, prostration and progressive weight loss. Clinical, laboratory and ultrasonographic evidence suggested the presence of glomerulonephropathy, which was confirmed by histopathological examination. The two dogs, given the severity of the condition, died. Histopathological analysis showed deposition of fibrillar proteinaceous material in the glomerular and tubular region, as well as lymphoplasmocytic infiltrate, characteristic of renal amyloidosis. It is essential to remember that family renal amyloidosis in dogs is a complex disease and that the origins must be investigated. The treatment is challenging, given the lack of a defined therapeutic management for the disease, which is often ineffective. Empathy and care in managing this condition can help improve the patient's quality of life and provide comfort to the owner during this challenging process.

La amiloidosis renal familiar es una enfermedad poco común en perros, que afecta a los riñones y se asocia con la acumulación anormal de proteínas amiloides, con capacidad de promover daño orgánico progresivo con compromiso de la funcionalidad. Caracterizada por la presencia de contenido proteico glomerular, la amiloidosis suele asociarse a insuficiencia renal, con la presencia de signos clínicos variados, siendo una afección grave y compleja. El presente artículo tiene como objetivo describir los hallazgos clínico-laboratorios, imagenológicos e histopatológicos de la amiloidosis familiar en dos perros Sharpei. Los animales estaban directamente emparentados y presentaban signos de cansancio, postración y pérdida progresiva de peso. Los datos clínico-laboratorios y ecográficos sugirieron la presencia de glomerulonefropatía, la cual fue confirmada mediante examen histopatológico. Los dos perros, dada la gravedad del cuadro, fallecieron. El análisis histopatológico mostró depósito de material proteico fibrilar en la región glomerular y tubular, así como infiltrado linfoplasmocitario, característico de la amiloidosis renal. Es fundamental recordar que la amiloidosis renal familiar en perros es una enfermedad compleja y que es necesario investigar sus orígenes. El tratamiento es un desafío, dada la falta de un manejo terapéutico definido para la enfermedad, que muchas veces resulta ineficaz. La empatía y el cuidado en el manejo de esta afección pueden ayudar a mejorar la calidad de vida del paciente y brindar comodidad al propietario durante este desafiante proceso.

Herpes Simplex Virus 1 Infection Does Not Increase Amyloid-ß Pathology in APP/PS1 Mice.

Using APP/PS1 mice that overproduce amyloid-ß (Aß) peptides, we investigated whether intranasal infection with a neurovirulent clinical strain of herpes simplex virus 1 (HSV-1) before Aß deposition could accelerate or increase Alzheimer's disease-like pathology. After HSV-1 infection, APP/PS1 mice presented a similar disease as wild type animals based on body weight changes, clinical symptoms, and survival rates. The number and volume of Aß plaques, the number of microglia, and the percentages of circulating monocyte subsets were similar in APP/PS1 mice infected or not with HSV-1. Thus, intranasal infection with HSV-1 does not alter Aß pathology in this mouse model.