Therapeutic potential of SSZ in modulating Alzheimer’s disease pathology: A multi-targeted experimental approach

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

Tau Pathology Generated by Overexpression of Tau

Relationship Between Tau Pathology and Neuroinflammation in Alzheimer's Disease

Emerging evidence suggests that metabolic and hormonal disturbances in polycystic ovary syndrome (PCOS) may increase vulnerability to neurodegenerative disorders. However, the link between PCOS and Alzheimer's disease (AD)-related pathology remains unclear. In this cross-sectional study, plasma levels of β-amyloid (Aβ40, Aβ42), phosphorylated tau (p-tau181), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were quantified in women with PCOS and age-matched controls. Homeostasis model assessment of insulin resistance (HOMA-IR), inflammatory cytokines (IL-6, TNF-α) and hormonal parameters were assessed. Mediation and moderation analyses were conducted to explore metabolic and hormonal pathways underlying biomarker alterations. Among 400 women (200 PCOS, 200 controls), age and BMI were comparable (P > 0.05). Compared with controls, PCOS participants had increased Aβ40, p-tau181, NfL and GFAP, a slightly higher Aβ42, and a lower Aβ42/40 ratio (all P < 0.05). p-tau181 correlated positively with HOMA-IR (r = 0.41) and IL-6 (r = 0.36), while Aβ42/40 ratio correlated negatively with HOMA-IR (r = -0.27). In multivariable analysis, p-tau181 (aOR = 1.34, 95% CI 1.05-1.71), IL-6 (aOR = 1.19) and TNF-α (aOR = 1.14) were independent predictors of insulin resistance. Mediation analysis indicated that HOMA-IR, IL-6 and TNF-α jointly mediated ∼ 71% of the PCOS-p-tau181 association, suggesting a metabolic-inflammatory pathway linking PCOS to AD-related tau pathology. PCOS is linked to peripheral markers of early Alzheimer's pathology, largely mediated by insulin resistance and inflammation. PCOS may provide a clinical context to explore metabolic-inflammatory contributors to early neurodegenerative changes.

Alzheimer´s disease (AD) is characterized by a progressive cognitive decline that correlates with the levels of amyloid β-peptide (Aβ) oligomers. Strong evidences connect changes of oligodendrocyte function with the onset of neurodegeneration in AD. However, the mechanisms controlling oligodendrocyte responses to Aβ are still elusive. Here, we tested the role of Aβ in oligodendrocyte differentiation, maturation, and survival in isolated oligodendrocytes and in organotypic cerebellar slices. We found that Aβ peptides specifically induced local translation of 18.5-kDa myelin basic protein (MBP) isoform in distal cell processes concomitant with an increase of process complexity of MBP-expressing oligodendrocytes. Aβ oligomers required integrin β1 receptor, Src-family kinase Fyn and Ca2+/CaMKII as effectors to modulate MBP protein expression. The pharmacological inhibition of Fyn kinase also attenuated oligodendrocyte differentiation and survival induced by Aβ oligomers. Similarly, using ex vivo organotypic cerebellar slices Aβ promoted MBP upregulation through Fyn kinase, and modulated oligodendrocyte population dynamics by inducing cell proliferation and differentiation. Importantly, application of Aβ to cerebellar organotypic slices enhanced remyelination and oligodendrocyte lineage recovery in lysolecithin (LPC)-induced demyelination. These data reveal an important role of Aβ in oligodendrocyte lineage function and maturation, which may be relevant to AD pathogenesis.

PTI-125 Reduces Biomarkers of Alzheimer's Disease in Patients.

Alzheimer's disease is a neurodegenerative disorder characterized by progressive cognitive decline, memory loss, and the formation of amyloid-beta plaques and tau tangles in the brain. This chronic condition has no known cure, and its progression varies greatly between individuals, eventually leading to severe cognitive impairment, loss of independence, and death. Microglia, the primary immune cells in the central nervous system that serve as the brain's first line of defense, are central to Alzheimer's disease pathology. Microglia play an important role in the response to injury and infection, as well as the regulation of amyloid-beta levels. However, when amyloid-beta accumulates, it activates an inflammatory response via microglia. While this response is initially protective, it may become chronic, contributing to the neuroinflammation that worsens Alzheimers disease pathology. In this study, I wanted to isolate and investigate the specific effects of M1 and M2 macrophages in the brains of genetically modified mice. Using CRISPR technology, we developed mouse models with selective expression of M1 macrophages without M2, M2 macrophages without M1, and models with both macrophage types. Western blot analysis quantified the levels of amyloid-beta in these mice, revealing how microglial activity influences Alzheimer's disease progression. Our findings show that M1 macrophages primarily regulate amyloid-beta through inflammatory processes, which may increase amyloid-beta production, whereas M2 macrophages are essential for amyloid-beta clearance. These findings emphasize the importance of balancing M1 and M2 macrophage activity when treating Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia and is defined as a progressive neurodegenerative disease. Main clinical features of AD are progressive impairment in learning and memory loss. Several studies have indicated that mitochondria play a critical role in the pathogenesis of AD. In this study, we investigated the effect of melatonin on mitochondria-dependent TRPA1 ion channels in neuroblastoma cells by creating an in vitro model of Alzheimer's disease. Okadaic acid was applied to SH-SY5Y (human neuroblastoma cell line) cells to create an AD model. After cellular differentiation, the following 7 main groups were created: Group 1 (Control), Group 2 (Mel+AD), Group 3 (Mel+AD+AP18), Group 4 (AD), Group 5 (AD+AP18), Group 6 (AD+Mel), and Group 7 (AD+Mel+AP18), and Alzheimer's disease was determined in vitro by examining the effect of melatonin on calcium-dependent TRPA1 channels in neuroblastoma cells. The Ca2+concentration was greater in the melatonin+AD, AD and AD+melatonin groups than in the control (p<0.001). However, there was no statistically significant difference between Mel+AD+AP18, AD+Mel+AP18 and the control. We determined that Ca2+ levels were lower in the melatonin+AD and AD+melatonin groups than in the AD group (p<0.001 and p<0.05). Additionally, cytosolic Ca2+ concentrations were found to be lower in the melatonin+AD group than in the AD+melatonin group (p<0.05). In evaluating the apoptosis and oxidative stress levels, we found that the apoptosis and intracellular ROS values were higher in the melatonin+AD, AD and AD+melatonin groups than in the control (p<0.001). In this respect, the mitochondrial depolarization and caspase-3 and caspase-9 levels were higher in the melatonin+AD, AD and AD+melatonin groups than in the control group (p<0.001). Additionally, the mitochondrial depolarization, caspase-3 and caspase-9 values were higher in the AD group than in the melatonin+AD and AD+melatonin groups (p<0.001), while mitochondrial depolarization and caspase-3 levels were lower in the melatonin+AD group than in the AD+melatonin group (p<0.001). However, in the same groups, there was no statistically significant difference in caspase-9 results. Additionally, the caspase-9 values were lower in the melatonin+AD group, AD group and AD+melatonin groups than in the melatonin+AD+AP18, AD+AP18 and AD+melatonin+AP18 groups, respectively (p<0.001 and p<0.05). Our results suggest that melatonin may be an effective option in the treatment and prophylaxis of Alzheimer's disease by reducing cytosolic Ca2+ concentration, apoptosis and intracellular ROS through TRPA1 channels.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline and is traditionally associated with grey matter pathology. Recent research highlights the significance of white matter and myelin damage in AD, presenting a paradigm shift in understanding the disease. The aim of this study was to summarize current advancements in magnetic resonance imaging (MRI) techniques and their applications in assessing myelin and brain pathology in AD with a special focus on ultrashort echo time (UTE) based techniques, alongside the role of artificial intelligence (AI) in enhancing diagnostic accuracy. Between April and May 2024, we conducted a literature search using Google Scholar, Web of Science, and PubMed, focusing on publications from 1990 to 2024. Search terms included "Quantitative imaging", "Alzheimer's MRI", "T1ρ Alzheimer's", "MT imaging Alzheimer's", and "myelin water fraction Alzheimer's". We included quantitative MRI studies involving AD brains and excluded volumetric analyses, non-quantitative studies, non-English reports, non-peer-reviewed studies, and animal research. Quantitative MRI techniques, including T1, T1ρ, magnetization transfer ratio (MTR), T2, T2*, susceptibility, myelin water fraction (MWF), and non-aqueous myelin proton density (PD) were described. These biomarkers represent different pathophysiological elements of brain damage and may have distinct functions at different phases of the disease. The role of AI in enhancing diagnostic accuracy is also discussed. In conclusion, integrating advanced MRI techniques and AI offers promising avenues for understanding and diagnosing AD. The focus on myelin damage and white matter integrity underscores the importance of comprehensive imaging approaches. Continued research and development are essential to address current challenges and improve clinical practice in AD diagnostics.

Emerging plasma biomarkers of Alzheimer's disease might be non-invasive tools to trace early Alzheimer's disease-related abnormalities such as the accumulation of amyloid-beta peptides, neurofibrillary tau tangles, glial activation and neurodegeneration. It is, however, unclear which pathological processes in the CNS can be adequately detected by peripheral measurements and whether plasma biomarkers are equally applicable in both clinical and preclinical phases. Here we aimed to explore the timing and performance of plasma biomarkers in mutation carriers compared to non-carriers in autosomal dominant Alzheimer's disease.Samples (n = 164) from mutation carriers (n = 33) and non-carriers (n = 42) in a Swedish cohort of autosomal dominant Alzheimer's disease (APP p.KM670/671NL, APP p.E693G and PSEN1 p.H163Y) were included in explorative longitudinal analyses. Plasma phosphorylated tau (P-tau181), total tau (T-tau), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) concentrations were measured with a single-molecule array method as previously described. Plasma biomarkers were additionally correlated to Alzheimer's disease core biomarkers in the CSF.Results from the longitudinal analyses confirmed that plasma P-tau181, NfL and GFAP concentrations were higher in mutation carriers compared to non-carriers. This change was observed in the presymptomatic phase and detectable first as an increase in GFAP approximately 10 years before estimated symptom onset, followed by increased levels of P-tau181 and NfL closer to expected onset. Plasma P-tau181 levels were correlated to levels of P-tau181 and T-tau in the CSF.Altogether, plasma P-tau181, GFAP and NfL seem to be feasible biomarkers to detect different Alzheimer's disease-related pathologies already in presymptomatic individuals. Interestingly, changes in plasma GFAP concentrations were detected prior to P-tau181 and NfL. Our results suggest that plasma GFAP might reflect Alzheimer's disease pathology upstream to accumulation of tangles and neurodegeneration. The implications of these findings need additional validation, in particular because of the limited sample size.

Background: Alzheimer’s disease (AD) is one of the most significant public health concerns and tremendous economic challenges. Studies conducted over the past decades show that exposure to radiofrequency electromagnetic fields (RF-EMFs) may relieve AD symptoms.Objective: To determine if exposure to RF-EMFs emitted by cellphones affect the risk of AD.Material and Methods: In this review, all relevant published articles reporting an association of cell phone use with AD were studied. We systematically searched international datasets to identify relevant studies. Finally, 33 studies were included in the review. Our review discusses the effects of RF-EMFs on the amyloid β (Aβ), oxidative stress, apoptosis, reactive oxygen species (ROS), neuronal death, and astrocyte responses. Moreover, the role of exposure parameters, including the type of exposure, its duration, and specific absorption rate (SAR), are discussed.Results: Progressive factors of AD such as Aβ, myelin basic protein (MBP), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and neurofilament light polypeptide (NFL) were decreased. While tau protein showed no change, factors affecting brain activity such as glial fibrillary acidic protein (GFAP), mitogen-activated protein kinases (MAPKs), cerebral blood flow (CBF), brain temperature, and neuronal activity were increased.Conclusion: Exposure to low levels of RF-EMFs can reduce the risk of AD by increasing MAPK and GFAP and decreasing MBP. Considering the role of apoptosis in AD and the effect of RF-EMF on the progression of the process, this review indicates the positive effect of these exposures.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by parkinsonism, cerebellar dysfunction, and autonomic failure. Key pathological features of MSA include the formation of glial cytoplasmic inclusions (GCIs) in oligodendrocytes (OLs), myelin loss, and neuroinflammation. Although both inflammation and myelination are known to be critical in MSA, the roles of myelin proteins and their relationship with inflammation have often been overlooked. In this study, we injected AAV-Olig001 vectors carrying either human SNCA (AAV-hSNCA) or eGFP (AAV-eGFP) into the striatum of TgM83 transgenic mice, which express the A53T mutant form of human alpha-synuclein (αSyn), as well as into wild-type (WT) mice. We then assessed myelin protein expression and inflammatory responses. TgM83 mice injected with AAV-hSNCA exhibited demyelination, increased activation of microglia and astrocytes, and altered cytokine and chemokine profiles (including IL-1α, IL-10, IL-12(p40), CCL2, CCL3, CCL4, and CCL5), compared to both WT mice and TgM83 mice injected with AAV-eGFP. Interestingly, myelin basic protein (MBP) levels were significantly elevated around the injection site in TgM83 mice injected with AAV-hSNCA. Notably, we observed a positive correlation between MBP expression and inflammatory markers, as indicated by Iba1 and GFAP staining. These findings suggest that hSNCA overexpression is associated with increased MBP levels and enhanced inflammatory responses, implicating that MBP and myelination processes may play previously underappreciated roles in the pathogenesis of MSA.

Immunoreactive myelin basic protein (MBP) levels were measured in cerebrospinal fluid (CSF) samples taken from 57 patients with active hydrocephalus (age range 3 weeks to 60 years). Of these patients, 28 (49%) had elevated MBP values (greater than 4.5 ng/ml). Elevated MBP levels were found in 44% of patients with congenital hydrocephalus, 75% of patients with posttraumatic hydrocephalus, 80% of patients with normal-pressure hydrocephalus, and 83% of patients with porencephaly. Also associated with abnormal MBP levels was the ventricular size as measured by computerized tomography scanning (chi 2: p less than 0.05): 36% of the patients with small ventricles (ventricle:brain ratio 0 to 0.4:1) had elevated MBP in the CSF, whereas 61% of those with moderate ventricles (0.41 to 0.6:1 ratio) and 100% of those with large ventricles (0.61 to 0.85:1 ratio) had abnormal values. Only 33% of those with maximal hydrocephalus (0.86 to 1.0:1 ratio) had elevated MBP levels, perhaps because of dilution effects. In three patients in whom CSF was obtained simultaneously by ventricular and lumbar punctures, the ventricular fluid had a consistently higher concentration of MBP, suggesting a cerebral origin. It is concluded that active hydrocephalus produces significant periventricular demyelination, probably as the result of mechanical stretching.

Amyloid-β diurnal pattern: possible role of sleep in Alzheimer's disease pathogenesis

DOI: 10.17691/stm2015.7.3.19 Received August 20, 2014Y.К. Komleva, MD, PhD, Associate Professor, Department of Biochemistry with Courses of Medical, Pharmaceutical and Toxicological Chemistry;N.V. Kuvacheva, PhD, Associate Professor, Department of Biochemistry with Courses of Medical, Pharmaceutical and Toxicological Chemistry;О.L. Lopatina, PhD, Associate Professor, Department of Biochemistry with Courses of Medical, Pharmaceutical and Toxicological Chemistry;Ya.V. Gorina, PhD, Associate Professor, Department of Biochemistry with Courses of Medical, Pharmaceutical and Toxicological Chemistry;О.V. Frolova, Researcher, Scientific Research Institute of Molecular Medicine and Pathobiochemistry;Е.А. Teplyashina, Tutor, Department of Biochemistry with Courses of Medical, Pharmaceutical and Toxicological Chemistry;М.М. Petrova, MD, DSc, Professor, Head of the Department of Ambulatory Therapy, Family Medicine and Healthy Lifestyle;А.b. salmina, MD, DSc, Professor, Head of the Department of Biochemistry with Courses of Medical, Pharmaceutical and Toxicological Chemistry, Head of Scientific Research Institute of Molecular Medicine and PathobiochemistryKrasnoyarsk State Medical university named after Professor V.F. Voino-Yasenetksy, 1 Partizana Zheleznyaka St., Krasnoyarsk, 660022, Russian FederationThe review concerns the novel approaches to Alzheimer’s disease pathogenesis represented in modern scientific literature, and aims at studying new possible targets for targeted pharmacotherapy of different stages of neurodegeneration. The multi-factorial disease results in disability and the loss of memory and cognitive functions causing life quality deterioration and the loss of legal capacity. The situation seems to be critical due to the fact that the majority of approved pharmaceuticals have just a symptomatic action rather than an adequate effect. For this reason there is the search for new target molecules for pharmacological intervention. Moreover, novel pharmaceuticals with more selective effect are being developed now.Modern concepts of Alzheimer’s disease pathogenesis are based on the recognized significance of the following pathological processes: neuronal damage and death, impaired neurogenesis and cell-to-cell interactions, neuroinflammation and vasculopathy development, while the accumulation of damaged proteins can be both a trigger mechanism, and also the result of the mentioned events. Based on the above stated ideas, there being developed the pharmacological approaches aimed at preventing pathologically damaged proteins from accumulating in brain, arresting aberrant neurotransmission, the correction of neuroinflammation and impaired neurogenesis, as well as the recovery of cell-to-cell interactions.The use of adequate animal models of Alzheimer’s disease is one of promising approaches to the development of novel pharmacotherapeutical strategies.Key words: Alzheimer’s disease; neurodegeneration; target-molecules; pharmacotherapy of Alzheimer’s disease.For contacts: Salmina Alla Borisovna, e-mail: allasalmina@mail.ru