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Steroids Jul 2024Steroidal alkaloids are secondary metabolites that are often found in plants, fungi and sponges. These compounds are considered as a source of bioactive compounds for... (Review)
Review
Steroidal alkaloids are secondary metabolites that are often found in plants, fungi and sponges. These compounds are considered as a source of bioactive compounds for the treatment of chronic diseases, such as neurological disorder like Alzheimer's disease (AD). Some examples of alkaloid derivatives currently used to treat AD symptoms include galantamine, huperzine A, and other alkaloids. AD is a multifactorial disease caused by multiple factors such as inflammation, oxidative stress, and protein aggregation. Based on the various important neuroprotective activities and different pharmacological effects of steroidal alkaloids with polypharmacological modulatory effects, they can lead to the development of new drugs for the treatment of AD. There are limited studies on the involvement of steroidal alkaloids in AD. Therefore, the mechanisms and neuroprotective abilities of these compounds are still poorly understood. The purpose of this review article is to provide an overview of the mechanism, toxicity and neuroprotective benefits of steroidal alkaloids and to discuss future possibilities to improve the application of steroidal alkaloids as anti-AD agents. The therapeutic value and limitations of the steroidal alkaloid are investigated to provide new perspectives for future clinical development studies.
PubMed: 38959993
DOI: 10.1016/j.steroids.2024.109468 -
Bioorganic & Medicinal Chemistry Jun 2024Ample biologically active peptides have been found, identified and modified for use in drug discovery to date. However, several factors, such as low metabolic stability... (Review)
Review
Ample biologically active peptides have been found, identified and modified for use in drug discovery to date. However, several factors, such as low metabolic stability due to proteolysis and non-specific interactions with multiple off-target molecules, might limit the therapeutic use of peptides. To enhance the stability and/or bioactivity of peptides, the development of "peptidomimetics," which mimick peptide molecules, is considered to be idealistic. Hence, chloroalkene dipeptide isosteres (CADIs) was designed, and their synthetic methods have been developed by us. Briefly, in a CADI an amide bond in peptides is replaced with a chloroalkene structure. CADIs might be superior mimetics of amide bonds because the Van der Waals radii (VDR) and the electronegativity value of a chlorine atom are close to those of the replaced oxygen atom. By a developed method of the "liner synthesis", N-tert-butylsulfonyl protected CADIs can be synthesized via a key reaction involving diastereoselective allylic alkylation using organocopper reagents. On the other hand, by a developed method of the "convergent synthesis", N-fluorenylmethoxycarbonyl (Fmoc)-protected carboxylic acids can be also constructed based on N- and C-terminal analogues from corresponding amino acid starting materials via an Evans syn aldol reaction and the Ichikawa allylcyanate rearrangement reaction involving a [3.3] sigmatropic rearrangement. Notably, CADIs can also be applied for Fmoc-based solid-phase peptide synthesis and therefore introduced into bioactive peptides including as the Arg-Gly-Asp (RGD) peptide and the amyloid β fragment Lys-Leu-Val-Phe-Phe (KLVFF) peptide, which are correlated with cell attachment and Alzheimer's disease (AD), respectively. These CADI-containing peptidomimetics stabilized the conformation and enhanced the potency of the cyclic RGD peptide and the cyclic KLVFF peptide.
PubMed: 38959684
DOI: 10.1016/j.bmc.2024.117811 -
Complementary Therapies in Clinical... Jul 2024To investigate the effect of physical exercise alone and in combination with cognitive stimulation on cognition, physical function, and quality of life in patients with...
INTRODUCTION
To investigate the effect of physical exercise alone and in combination with cognitive stimulation on cognition, physical function, and quality of life in patients with Alzheimer's Disease (PwAD).
METHODS
The study was a randomized controlled, single-blinded trial with pre-and post-treatment and follow-up assessments conducted at the private hospital and home environment in PwAD. Seventy-five (N = 75) participants diagnosed with AD were enrolled, but sixty (N = 60) participants (mean age 77.8 years, standard deviation (SD) 6.7) were randomized as physical exercise group (PEG) (n = 20), physical exercise and cognitive stimulation group (PE + CSG) (n = 20) and control group (CG) (n = 20). Participants in PEG and PE + CSG performed an online supervised physical exercise program (SPEP) given biweekly for 12 weeks. Additionally, the cognitive stimulation (CS) program was offered for at least three or five days for 12 weeks for PE + CSG. No treatment was given for the CG. The primary outcome measures were cognition, balance, functional mobility (FM), upper extremity muscle strength (UEMS) and lower extremity muscle strength (LEMS), and quality of life (QoL). Furthermore, depression, basic activities of daily living (BADL) and instrumental activities of daily living (IADL) were measured secondarily.
RESULTS
PE + CSG demonstrated significant improvement in cognition, balance, FM, UEMS, IADL and reduction in depression compared to the CG (p < 0.05). Besides, participants in the PE + CSG had statistically superior QoL and IADL than the PEG (p < 0.05).
CONCLUSIONS
The addition of CS to the SPEP was a safe and effective method to gain statistically significant improvements in cognition, balance, FM, UEMS, IADL, and reduction in depression in PwAD.
PubMed: 38959564
DOI: 10.1016/j.ctcp.2024.101881 -
Science Translational Medicine Jul 2024Pathological tau aggregates cause cognitive decline in neurodegenerative tauopathies, including Alzheimer's disease (AD). These aggregates are prevalent within...
Pathological tau aggregates cause cognitive decline in neurodegenerative tauopathies, including Alzheimer's disease (AD). These aggregates are prevalent within intracellular compartments. Current tau immunotherapies have shown limited efficacy in clearing intracellular tau aggregates and improving cognition in clinical trials. In this study, we developed toxic tau conformation-specific monoclonal antibody-2 (TTCM2), which selectively recognized pathological tau aggregates in brain tissues from patients with AD, dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP). TTCM2 potently inhibited tau-seeding activity, an essential mechanism underlying tauopathy progression. To effectively target intracellular tau aggregates and ensure rapid delivery to the brain, TTCM2 was loaded in micelles (TTCM2-ms) and administered through the intranasal route. We found that intranasally administered TTCM2-ms efficiently entered the brain in hTau-tauopathy mice, targeting pathological tau in intracellular compartments. Moreover, a single intranasal dose of TTCM2-ms effectively cleared pathological tau, elevated synaptic proteins, and improved cognitive functions in aged tauopathy mice. Mechanistic studies revealed that TTCM2-ms cleared intracellular, synaptic, and seed-competent tau aggregates through tripartite motif-containing 21 (TRIM21), an intracellular antibody receptor and E3 ubiquitin ligase known to facilitate proteasomal degradation of cytosolic antibody-bound proteins. TRIM21 was found to be essential for TTCM2-ms-mediated clearance of tau pathology. Our study collectively provides evidence of the effectiveness of nasal tau immunotherapy in targeting and clearing intracellular tau pathology through TRIM21 and enhancing cognition in aged tauopathy mice. This study could be valuable in designing effective tau immunotherapies for AD and other tauopathies.
Topics: Animals; tau Proteins; Tauopathies; Administration, Intranasal; Immunotherapy; Cognition; Humans; Mice, Transgenic; Mice; Aging; Brain; Antibodies, Monoclonal; Disease Models, Animal; Protein Aggregates
PubMed: 38959324
DOI: 10.1126/scitranslmed.adj5958 -
JMIR Aging Jul 2024Usability is a key indicator of the quality of technology products. In tandem with technological advancements, potential use by individuals with dementia is increasing.... (Review)
Review
BACKGROUND
Usability is a key indicator of the quality of technology products. In tandem with technological advancements, potential use by individuals with dementia is increasing. However, defining the usability of technology for individuals with dementia remains an ongoing challenge. The diverse and progressive nature of dementia adds complexity to the creation of universal usability criteria, highlighting the need for focused deliberations. Technological interventions offer potential benefits for people living with dementia and caregivers. Amid COVID-19, technology's role in health care access is growing, especially among older adults. Enabling the diverse population of people living with dementia to enjoy the benefits of technologies requires particular attention to their needs, desires, capabilities, and vulnerabilities to potential harm from technologies. Successful technological interventions for dementia require meticulous consideration of technology usability.
OBJECTIVE
This concept analysis aims to examine the usability of technology in the context of individuals living with dementia to establish a clear definition for usability within this specific demographic.
METHODS
The framework by Walker and Avant was used to guide this concept analysis. We conducted a literature review spanning 1984 to 2024, exploring technology usability for people with dementia through the PubMed, Web of Science, and Google Scholar databases using the keywords "technology usability" and "dementia." We also incorporated clinical definitions and integrated interview data from 29 dyads comprising individuals with mild Alzheimer dementia and their respective care partners, resulting in a total of 58 older adults. This approach aimed to offer a more comprehensive portrayal of the usability needs of individuals living with dementia, emphasizing practical application.
RESULTS
The evidence from the literature review unveiled that usability encompasses attributes such as acceptable learnability, efficiency, and satisfaction. The clinical perspective on dementia stages, subtypes, and symptoms underscores the importance of tailored technology usability assessment. Feedback from 29 dyads also emphasized the value of simplicity, clear navigation, age-sensitive design, personalized features, and audio support. Thus, design should prioritize personalized assistance for individuals living with dementia, moving away from standardized technological approaches. Synthesized from various sources, the defined usability attributes for individuals living with dementia not only encompass the general usability properties of effectiveness, efficiency, and satisfaction but also include other key factors: adaptability, personalization, intuitiveness, and simplicity, to ensure that technology is supportive and yields tangible benefits for this demographic.
CONCLUSIONS
Usability is crucial for people living with dementia when designing technological interventions. It necessitates an understanding of user characteristics, dementia stages, symptoms, needs, and tasks, as well as consideration of varied physical requirements, potential sensory loss, and age-related changes. Disease progression requires adapting to evolving symptoms. Recommendations include versatile, multifunctional technology designs; accommodating diverse needs; and adjusting software functionalities for personalization. Product feature classification can be flexible based on user conditions.
Topics: Humans; Dementia; COVID-19; Aged; Female; Male; Caregivers; Aged, 80 and over
PubMed: 38959053
DOI: 10.2196/51987 -
JMIR MHealth and UHealth Jul 2024Lifestyle behaviors including exercise, sleep, diet, stress, mental stimulation, and social interaction significantly impact the likelihood of developing dementia....
BACKGROUND
Lifestyle behaviors including exercise, sleep, diet, stress, mental stimulation, and social interaction significantly impact the likelihood of developing dementia. Mobile health (mHealth) apps have been valuable tools in addressing these lifestyle behaviors for general health and well-being, and there is growing recognition of their potential use for brain health and dementia prevention. Effective apps must be evidence-based and safeguard user data, addressing gaps in the current state of dementia-related mHealth apps.
OBJECTIVE
This study aims to describe the scope of available apps for dementia prevention and risk factors, highlighting gaps and suggesting a path forward for future development.
METHODS
A systematic search of mobile app stores, peer-reviewed literature, dementia and Alzheimer association websites, and browser searches was conducted from October 19, 2022, to November 2, 2022. A total of 1044 mHealth apps were retrieved. After screening, 152 apps met the inclusion criteria and were coded by paired, independent reviewers using an extraction framework. The framework was adapted from the Silberg scale, other scoping reviews of mHealth apps for similar populations, and background research on modifiable dementia risk factors. Coded elements included evidence-based and expert credibility, app features, lifestyle elements of focus, and privacy and security.
RESULTS
Of the 152 apps that met the final selection criteria, 88 (57.9%) addressed modifiable lifestyle behaviors associated with reducing dementia risk. However, many of these apps (59/152, 38.8%) only addressed one lifestyle behavior, with mental stimulation being the most frequently addressed. More than half (84/152, 55.2%) scored 2 points out of 9 on the Silberg scale, with a mean score of 2.4 (SD 1.0) points. Most of the 152 apps did not disclose essential information: 120 (78.9%) did not disclose expert consultation, 125 (82.2%) did not disclose evidence-based information, 146 (96.1%) did not disclose author credentials, and 134 (88.2%) did not disclose their information sources. In addition, 105 (69.2%) apps did not disclose adherence to data privacy and security practices.
CONCLUSIONS
There is an opportunity for mHealth apps to support individuals in engaging in behaviors linked to reducing dementia risk. While there is a market for these products, there is a lack of dementia-related apps focused on multiple lifestyle behaviors. Gaps in the rigor of app development regarding evidence base, credibility, and adherence to data privacy and security standards must be addressed. Following established and validated guidelines will be necessary for dementia-related apps to be effective and advance successfully.
Topics: Humans; Mobile Applications; Dementia; Alzheimer Disease; Telemedicine
PubMed: 38959029
DOI: 10.2196/50186 -
JAMA Psychiatry Jul 2024Subjective cognitive decline (SCD) is recognized to be in the Alzheimer disease (AD) cognitive continuum. The SCD Initiative International Working Group recently...
IMPORTANCE
Subjective cognitive decline (SCD) is recognized to be in the Alzheimer disease (AD) cognitive continuum. The SCD Initiative International Working Group recently proposed SCD-plus (SCD+) features that increase risk for future objective cognitive decline but that have not been assessed in a large community-based setting.
OBJECTIVE
To assess SCD risk for mild cognitive impairment (MCI), AD, and all-cause dementia, using SCD+ criteria among cognitively normal adults.
DESIGN, SETTING, AND PARTICIPANTS
The Framingham Heart Study, a community-based prospective cohort study, assessed SCD between 2005 and 2019, with up to 12 years of follow-up. Participants 60 years and older with normal cognition at analytic baseline were included. Cox proportional hazards (CPH) models were adjusted for baseline age, sex, education, APOE ε4 status, and tertiles of AD polygenic risk score (PRS), excluding the APOE region. Data were analyzed from May 2021 to November 2023.
EXPOSURE
SCD was assessed longitudinally using a single question and considered present if endorsed at the last cognitively normal visit. It was treated as a time-varying variable, beginning at the first of consecutive, cognitively normal visits, including the last, at which it was endorsed.
MAIN OUTCOMES AND MEASURES
Consensus-diagnosed MCI, AD, and all-cause dementia.
RESULTS
This study included 3585 participants (mean [SD] baseline age, 68.0 [7.7] years; 1975 female [55.1%]). A total of 1596 participants (44.5%) had SCD, and 770 (21.5%) were carriers of APOE ε4. APOE ε4 and tertiles of AD PRS status did not significantly differ between the SCD and non-SCD groups. MCI, AD, and all-cause dementia were diagnosed in 236 participants (6.6%), 73 participants (2.0%), and 89 participants (2.5%), respectively, during follow-up. On average, SCD preceded MCI by 4.4 years, AD by 6.8 years, and all-cause dementia by 6.9 years. SCD was significantly associated with survival time to MCI (hazard ratio [HR], 1.57; 95% CI, 1.22-2.03; P <.001), AD (HR, 2.98; 95% CI, 1.89-4.70; P <.001), and all-cause dementia (HR, 2.14; 95% CI, 1.44-3.18; P <.001). After adjustment for APOE and AD PRS, the hazards of SCD were largely unchanged.
CONCLUSIONS AND RELEVANCE
Results of this cohort study suggest that in a community setting, SCD reflecting SCD+ features was associated with an increased risk of future MCI, AD, and all-cause dementia with similar hazards estimated in clinic-based settings. SCD may be an independent risk factor for AD and other dementias beyond the risk incurred by APOE ε4 and AD PRS.
PubMed: 38959008
DOI: 10.1001/jamapsychiatry.2024.1678 -
Molecular Neurobiology Jul 2024As a risk factor for Alzheimer's disease (AD), studies have demonstrated that long-term high-fat diet (HFD) could accelerate the deposition of amyloid beta (Aβ) in the...
As a risk factor for Alzheimer's disease (AD), studies have demonstrated that long-term high-fat diet (HFD) could accelerate the deposition of amyloid beta (Aβ) in the brain. The glymphatic system plays a critical role in Aβ clearance from the brain. However, studies investigating the effects of long-term HFD on glymphatic function have reported paradoxical outcomes, and whether glymphatic dysfunction is involved in the disturbance of Aβ clearance in long-term HFD-fed mice has not been determined. In the present study, we injected fluorescently labeled Aβ into the hippocampus and found that Aβ clearance was decreased in HFD-fed mice. We found that long-term HFD-fed mice had decreased glymphatic function by injecting fluorescent tracers into the cisterna magna and corpus striatum. In long-term HFD-fed mice, aquaporin-4 (AQP4) polarization in the cortex was disrupted, and glymphatic clearance activity was positively correlated with the AQP4 polarization index. In HFD-fed mice, the disturbance of Aβ clearance from the hippocampus was exacerbated by TGN-020, a specific inhibitor of AQP4, whereas TGN-073, an enhancer of AQP4, ameliorated it. These findings suggest that long-term HFD disrupts Aβ clearance by inhibiting AQP4-mediated glymphatic function. The underlying mechanism may involve the disruption of AQP4 polarization.
PubMed: 38958889
DOI: 10.1007/s12035-024-04320-3 -
Molecular Neurobiology Jul 2024Alzheimer's disease is a progressive neurodegenerative disorder that affects memory and cognitive abilities, affecting millions of people around the world. Current... (Review)
Review
Alzheimer's disease is a progressive neurodegenerative disorder that affects memory and cognitive abilities, affecting millions of people around the world. Current treatments focus on the management of symptoms, as no effective therapy has been approved to modify the underlying disease process. Gene therapy is a promising approach that can offer disease-modifying treatment for AD, targeting various aspects of the pathophysiology of the disease. This review presents a comprehensive overview of the current state of gene therapy research for AD, with a specific focus on clinical trials and preclinical studies that have used nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), apolipoprotein E2 (APOE2), and human telomerase reverse transcriptase (hTERT) as therapeutic gene therapy approaches. These gene targets have shown potential to alleviate the neuropathology of AD in animal studies and have demonstrated feasibility and safety in non-human primates. Despite the failure of the NGF gene therapy approach in clinical trials, we have reviewed and highlighted the reported findings and evaluations from the trials. Furthermore, the review included the conclusions of postmortem brain tissue analysis of AD patients who received NGF gene therapy. The goal is to learn from the failed trials and improve the approach in the future. Although gene therapy shows promise, it faces several challenges and limitations, including optimizing gene delivery methods, enhancing safety and efficacy profiles, and determining long-term results. This review contributes to the growing body of literature on innovative treatments for AD and highlights the need for more research and development to advance gene therapy as a viable treatment option for AD.
PubMed: 38958888
DOI: 10.1007/s12035-024-04285-3 -
Journal of Molecular Neuroscience : MN Jul 2024Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide and has a great socio-economic impact. Modified oxidative lipid metabolism and... (Review)
Review
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide and has a great socio-economic impact. Modified oxidative lipid metabolism and dysregulated iron homeostasis have been implicated in the pathogenesis of this disorder, but the detailed pathophysiological mechanisms still remain unclear. Apolipoprotein E (APOE) is a lipid-binding protein that occurs in large quantities in human blood plasma, and a polymorphism of the APOE gene locus has been identified as risk factors for AD. The human genome involves three major APOE alleles (APOE2, APOE3, APOE4), which encode for three subtly distinct apolipoprotein E isoforms (APOE2, APOE3, APOE4). The canonic function of these apolipoproteins is lipid transport in blood and brain, but APOE4 allele carriers have a much higher risk for AD. In fact, about 60% of clinically diagnosed AD patients carry at least one APOE4 allele in their genomes. Although the APOE4 protein has been implicated in pathophysiological key processes of AD, such as extracellular beta-amyloid (Aβ) aggregation, mitochondrial dysfunction, neuroinflammation, formation of neurofibrillary tangles, modified oxidative lipid metabolism, and ferroptotic cell death, the underlying molecular mechanisms are still not well understood. As for all mammalian cells, iron plays a crucial role in neuronal functions and dysregulation of iron homeostasis has also been implicated in the pathogenesis of AD. Imbalances in iron homeostasis and impairment of the hydroperoxy lipid-reducing capacity induce cellular dysfunction leading to neuronal ferroptosis. In this review, we summarize the current knowledge on APOE4-related oxidative lipid metabolism and the potential role of ferroptosis in the pathogenesis of AD. Pharmacological interference with these processes might offer innovative strategies for therapeutic interventions.
Topics: Humans; Alzheimer Disease; Ferroptosis; Lipid Metabolism; Apolipoprotein E4; Animals; Iron
PubMed: 38958788
DOI: 10.1007/s12031-024-02224-4