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Chemical & Pharmaceutical Bulletin 2024Amyloid-β (Aβ) plaques and neurofibrillary tangles containing phosphorylated tau protein are major hallmarks of Alzheimer's disease (AD). Drug discovery efforts to... (Review)
Review
Amyloid-β (Aβ) plaques and neurofibrillary tangles containing phosphorylated tau protein are major hallmarks of Alzheimer's disease (AD). Drug discovery efforts to target Aβ and tau have been the primary focus for several decades. Recently, substantial breakthroughs have been achieved in the clinical development of Aβ antibodies; aducanumab was approved under conditional accelerated pathway by Food and Drug Administration (FDA) in the U.S. as the first disease-modifying agent for treating AD, and lecanemab has been granted traditional full approved in the U.S. and Japan. In addition, donanemab met the primary endpoint in a phase 3 study. On the other hand, tau-targeting therapies have failed to show clinical benefit although that increased tau levels show a strong correlation with cognitive impairment relative to Aβ depositions. Currently, tau immunotherapies, such as anti-tau antibodies and tau vaccines, have shown functional benefits in clinical trials. Also, clinical trials for combination therapy of Aβ and tau antibodies to see their potential are being investigated. In this review, we provide updates on the results of clinical trials of anti-Aβ antibodies and anti-tau therapeutics and suggest future directions for these therapeutics.
Topics: Alzheimer Disease; Humans; tau Proteins; Amyloid beta-Peptides; Immunotherapy; Animals
PubMed: 38945936
DOI: 10.1248/cpb.c24-00069 -
Journal of Nutritional Science and... 2024Pyridoxamine (PM) is one of the natural vitamins B6 (VB6) and functions as an endogenous inhibitor for the formation of AGEs (advanced glycation end products). The AGEs...
Pyridoxamine (PM) is one of the natural vitamins B6 (VB6) and functions as an endogenous inhibitor for the formation of AGEs (advanced glycation end products). The AGEs are implicated in aging, diabetes, and various neuropsychiatric disease, including schizophrenia, Alzheimer's disease, and Parkinson's disease. However, it is unclear whether the absence of PM per se accumulates AGEs in vivo and causes behavioral dysfunctions. To address these points, we raised PM-deficient fruit flies, Drosophila melanogaster, with the sterilized defined medium. Flies reared in a PM-deficient medium accumulated AGEs and reduced lifespan, impaired gustatory response, sleep, courtship behavior, and olfactory learning. These results suggest that PM suppresses AGE accumulation in vivo and is required for regulating innate and empirical behaviors.
Topics: Animals; Drosophila melanogaster; Glycation End Products, Advanced; Pyridoxamine; Behavior, Animal; Longevity; Male; Sleep; Female; Sexual Behavior, Animal; Learning
PubMed: 38945891
DOI: 10.3177/jnsv.70.252 -
Advances in Gerontology = Uspekhi... 2024Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by progressive cognitive decline. This review discusses current therapeutic... (Review)
Review
Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by progressive cognitive decline. This review discusses current therapeutic strategies for the treatment of Alzheimer's disease, their limitations, and potential prospects. The feasibility of comprehensive approach for AD therapy is considered in contrast to the classical method in the development of therapeutic strategy. Leu-Ile, Glu-Trp, Lys-Glu, Gly-Pro, Glu-Asp-Arg, Lys-Glu-Asp, Met-Glu-His-Phe-Pro-Gly-Pro short peptides are described as multitarget agents with a wide range of activity.
Topics: Alzheimer Disease; Humans; Oligopeptides
PubMed: 38944767
DOI: No ID Found -
Nature Reviews. Neurology Jun 2024
PubMed: 38944654
DOI: 10.1038/s41582-024-00976-6 -
Seizure Jun 2024The unique patho-clinical entity of late-onset epilepsy (LOE), distinguished by its distinct natural history, from its onset to the prognosis it portends, necessitates... (Review)
Review
The unique patho-clinical entity of late-onset epilepsy (LOE), distinguished by its distinct natural history, from its onset to the prognosis it portends, necessitates specialized care. We lack a universally accepted definition, but LOE is typically identified as epilepsy onset after the age of 60 or 65. Unlike epilepsy in younger individuals, LOE is almost by default focal in origin, secondary to acquired etiologies, and presents unique diagnostic and management challenges due to its atypical semiology, higher comorbidity burden, frailty, and increased risks of subsequent stroke and dementia. LOE clinics have been established to address these challenges, providing a multidisciplinary approach to optimize outcomes in patients with new-onset seizures beyond the fifth decade of life. LOE clinics are essential for comprehensive care, offering not only seizure management but also monitoring and addressing associated comorbidities. The care model involves collaboration among neurologists, primary care providers, cardiologists, mental health professionals, and social workers to manage LOE patients' complex needs effectively. The prevalence of cognitive dysfunction in LOE patients underscores the need for regular cognitive assessments and interventions. Biomarker research, particularly involving amyloid beta, offers promising avenues for early diagnosis and a better understanding of the interplay between LOE and Alzheimer's disease. Establishing LOE clinics in major referral centers can enhance provider expertise, improve patient outcomes, and facilitate research to advance diagnostic and therapeutic strategies. In conclusion, LOE clinics play a critical role in addressing the multifaceted needs of older adults with epilepsy, tailored to local resources and challenges, thus enhancing epilepsy care in an aging global population.
PubMed: 38944548
DOI: 10.1016/j.seizure.2024.06.026 -
Mitochondrion Jun 2024Mitochondria are singular cell organelles essential for many cellular functions, which includes responding to stress, regulating calcium levels, maintaining protein... (Review)
Review
Mitochondria are singular cell organelles essential for many cellular functions, which includes responding to stress, regulating calcium levels, maintaining protein homeostasis, and coordinating apoptosis response. The vitality of cells, therefore, hinges on the optimal functioning of these dynamic organelles. Mitochondrial Quality Control Mechanisms (MQCM) play a pivotal role in ensuring the integrity and functionality of mitochondria. Perturbations in these mechanisms have been closely associated with the pathogenesis of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Compelling evidence suggests that targeting specific pathways within the MQCM could potentially offer a therapeutic avenue for rescuing mitochondrial integrity and mitigating the progression of neurodegenerative diseases. The intricate interplay of cellular stress, protein misfolding, and impaired quality control mechanisms provides a nuanced understanding of the underlying pathology. Consequently, unravelling the specific MQCM dysregulation in neurodegenerative disorders becomes paramount for developing targeted therapeutic strategies. This review delves into the impaired MQCM pathways implicated in neurodegenerative disorders and explores emerging therapeutic interventions. By shedding light on pharmaceutical and genetic manipulations aimed at restoring MQCM efficiency, the discussion aims to provide insights into novel strategies for ameliorating the progression of neurodegenerative diseases. Understanding and addressing mitochondrial quality control mechanisms not only underscore their significance in cellular health but also offer a promising frontier for advancing therapeutic approaches in the realm of neurodegenerative disorders.
PubMed: 38944367
DOI: 10.1016/j.mito.2024.101926 -
Journal of Ethnopharmacology Jun 2024Lindera aggregata (Sims) Kosterm is a common traditional herb that has multiple bioactivities. Radix Linderae (LR), the dry roots of Lindera aggregata (Sims) Kosterm.,...
ETHNOPHARMACOLOGICAL RELEVANCE
Lindera aggregata (Sims) Kosterm is a common traditional herb that has multiple bioactivities. Radix Linderae (LR), the dry roots of Lindera aggregata (Sims) Kosterm., is a traditional Chinese herbal medicine with antioxidant, anti-inflammatory and immunomodulatory properties, first found in Kaibao Era. Norboldine (Nor) is an alkaloid extracted from LR and is one of the primary active ingredients of LR. However, the pharmacological functions of Nor in Alzheimer's disease (AD) and the mechanism of action are unknown.
AIM OF THE STUDY
This study aims to investigate the effect and mechanism of Nor therapy in improving the cognitive impairment and pathological features of 3×Tg mice.
MATERIALS AND METHODS
3×Tg mice were treated with two concentrations of Nor for 1 month. Memory and cognitive abilities of mice were assessed by novel object recognition experiment and Morris water maze, followed by the impact of Nor on the pathology of AD by immunofluorescence. The protective effect of Nor on neuronal apoptosis was examined in PC12 cells and animal tissues using Western blotting and other experiments. Finally, Western blotting was used to jointly verify the anti-apoptotic effect of Nor by activating AMPK/GSK3β/Nrf2 signaling pathway at animal and cellular levels.
RESULTS
In this study, we showed that Nor treatment improved the capacity of the learning and memory of 3×Tg mice and alleviated AD-related pathology such as Aβ deposition. In addition, Nor restored the abnormalities of mitochondrial membrane potential, significantly reduced the production of intracellular ROS and neuronal apoptosis. Mechanistically, we combined network pharmacology and experimental verification to show that Nor may exert antioxidant stress and anti-apoptotic through the AMPK/GSK3β/Nrf2 signaling pathway.
CONCLUSION
Our data provide some evidence that Nor exerts a neuroprotective effect through the AMPK/GSK3β/Nrf2 pathway, thereby improving behavioral cognitive impairment in AD model mice. Natural products derived from traditional Chinese medicines are becoming increasingly popular in the process of new drug development and discovery, and our findings provide new perspectives for the discovery of improved treatment strategies for AD.
PubMed: 38944357
DOI: 10.1016/j.jep.2024.118498 -
Progress in Neuro-psychopharmacology &... Jun 2024The discovery that metabolic alterations often coexist with neurodegenerative conditions has sparked interest in the examination of metabolic regulatory factors as...
The discovery that metabolic alterations often coexist with neurodegenerative conditions has sparked interest in the examination of metabolic regulatory factors as potential modulators of brain health. Here, we examined the role of adipokines (leptin, adiponectin, resistin, and IL6) and insulin on different markers of brain atrophy in participants on the spectrum of Alzheimer's Disease. We included 566 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset with 1063 follow-up time points (average follow-up: one year); and examined the association between metabolic regulatory factors and volumetric MRI values, white matter hyperintensities, and measures of cognitive impairment. Higher leptin, resistin, IL6, and insulin were associated with markers of cerebral atrophy, such as lower total brain volume, or higher ventricular volume. Higher leptin and resistin were also associated with greater impairment in daily life activities. Higher adiponectin was associated with lower ventricle volume. There was no association between adipokines or insulin with white matter hyperintensities. Our findings indicate a co-occurrence between alterations in metabolic regulatory factors and in brain volume along the preclinical to clinical spectrum of Alzheimer's Disease. These results suggest that strategies aimed at promoting metabolic health may positively impact brain health.
PubMed: 38944333
DOI: 10.1016/j.pnpbp.2024.111077 -
Biological Psychiatry Jun 2024Most mental disorders involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), a recently evolved brain region that subserves working memory, abstraction and... (Review)
Review
Most mental disorders involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), a recently evolved brain region that subserves working memory, abstraction and the thoughtful regulation of attention, action and emotion. For example, schizophrenia, depression, long-COVID and Alzheimer's disease are all associated with dlPFC dysfunction, with neuropathology often focused in layer III. The dlPFC has extensive top-down projections: e.g. to the posterior association cortices to regulate attention, and the subgenual cingulate cortex via the rostral and medial PFC to regulate emotional responses. However, the dlPFC is particularly dependent on arousal state, and is very vulnerable to stress and inflammation, which are etiological and/or exacerbating factors in most mental disorders. The cellular mechanisms by which stress and inflammation impact the dlPFC are a topic of current research, and are summarized in this review. For example, the layer III dlPFC circuits generating working memory-related neuronal firing have unusual neurotransmission, depending on NMDAR and nicotinic-α7R actions that are blocked under inflammatory conditions by kynurenic acid. These circuits also have unusual neuromodulation, with the molecular machinery to magnify calcium signaling in spines needed to support persistent firing, which must be tightly regulated to prevent toxic calcium actions. Stress rapidly weakens layer III connectivity by driving feedforward calcium-cAMP opening of potassium channels on spines. This is regulated by postsynaptic noradrenergic α2A-AR and mGluR3 signaling, but dysregulated by inflammation and/or chronic stress exposure, contributing to spine loss. Treatments that strengthen dlPFC, via pharmacological (the α2A-AR agonist, guanfacine) or rTMS manipulation, provide a rational basis for therapy.
PubMed: 38944141
DOI: 10.1016/j.biopsych.2024.06.016 -
The Journal of Biological Chemistry Jun 2024The beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the predominant β-secretase, cleaving the amyloid precursor protein (APP) via the amyloidogenic...
The beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the predominant β-secretase, cleaving the amyloid precursor protein (APP) via the amyloidogenic pathway. In addition, BACE1 as an amyloid degrading enzyme (ADE), cleaves Aβ to produce the C-terminally truncated non-toxic Aβ fragment Aβ34 which is an indicator of amyloid clearance. Here, we analyzed effects of BACE1 inhibitors on its opposing enzymatic functions, i.e., amyloidogenic (Aβ producing) and amyloidolytic (Aβ degrading) activities, using cell culture models with varying BACE1/APP ratios. Under high level BACE1 expression, low-dose inhibition unexpectedly yielded a two-fold increase in Aβ42 and Aβ40 levels. The concomitant decrease in Aβ34 and secreted APPβ levels suggested that the elevated Aβ42 and Aβ40 levels were due to the attenuated Aβ degrading activity of BACE1. Notably, the amyloidolytic activity of BACE1 was impeded at lower BACE1 inhibitor concentrations compared to its amyloidogenic activity, thereby suggesting that the Aβ degrading activity of BACE1 was more sensitive to inhibition than its Aβ producing activity. Under endogenous BACE1 and APP levels, "low-dose" BACE1 inhibition affected both the Aβ producing and degrading activities of BACE1, i.e., significantly increased Aβ42/Aβ40 ratio and decreased Aβ34 levels, respectively. Further, we incubated recombinant BACE1 with synthetic Aβ peptides and found that BACE1 has higher affinity for Aβ substrates over APP. In summary, our results suggest that stimulating BACE1's ADE activity and halting Aβ production without decreasing Aβ clearance could still be a promising therapeutic approach with new, yet to be developed, BACE1 modulators.
PubMed: 38944120
DOI: 10.1016/j.jbc.2024.107510