Repetitive Transcranial Magnetic Stimulation Decreases Serum Amyloid-ß and Increases Ectodomain of p75 Neurotrophin Receptor in Patients with Alzheimer's Disease.

BACKGROUND: This study investigated the impact of repetitive transcranial magnetic stimulation (rTMS) on serum levels of Amyloid-ß (Aß) as well as the ectodomain of p75 neurotrophin receptor (p75ECD) in patients with Alzheimer's disease (AD). METHODS: A total of 46 patients diagnosed with AD between June 1, 2020 and December 31, 2021 were randomized to undergo either 20 Hz rTMS treatment of the left dorsolateral prefrontal cortex (DLPFC) or sham procedure. Cognitive function and activity of daily living were evaluated. Neuropsychological tests and blood samples were gathered at baseline and at 2, 3, 4, and 6 weeks after rTMS therapy. RESULTS: There were no evident differences between rTMS group and sham group in serum Aß40, Aß42, total Aß, ApoE, and p75ECD standards at baseline (p > 0.05). Serum levels of Aß40, Aß42, as well as total Aß, were significantly lower in the rTMS group at 3, 4 and 6 weeks relative to the sham group (p < 0.05). Serum p75ECD levels in the rTMS group were significantly higher than those of the sham group at 3, 4 and 6 weeks (p < 0.05). Levels of serum Aß40 (r: -0.78, -0.83, -0.68, respectively), Aß42 (r: -0.76, -0.76, -0.61, respectively) and total Aß (r: -0.74, -0.81, -0.66, respectively) were negatively correlated with MoCA, MMSE and MBI scores, while serum p75ECD levels (r: 0.84, 0.90, 0.72, respectively) were positively correlated (p < 0.01). The level of serum Aß40 (r = 0.77), Aß42 (r = 0.69) as well as total Aß (r = 0.73) were positively correlated with ADAS-cog score, while p75ECD levels (r = -0.86) were negatively correlated (p < 0.01). CONCLUSIONS: The results of this study suggest that rTMS may decrease serum Aß levels and increase serum p75ECD levels in patients with AD, offering insight into a potential underpinning mechanism of rTMS.

[Therapeutic monitoring and prediction of the efficacy of neurotrophic treatment in patients with amnestic type of mild cognitive impairment]. / Terapevticheskii monitoring i prognoz éffektivnosti neirotroficheskoi terapii u patsientov s sindromom miagkogo kognitivnogo snizheniia amnesticheskogo tipa.

AIM: To perform therapeutic monitoring and prediction of the neurotrophic therapy efficacy in patients with amnestic type of mild cognitive impairment (aMCI) in a model of course cerebrolysin therapy. MATERIAL AND METHODS: The study involved a group of 19 elderly patients who met the diagnostic criteria of aMCI. All patients received a course of neurotrophic therapy consisting of 20 intravenous infusions of cerebrolysin (30 ml of cerebrolysin in 100 ml of isotonic sodium chloride solution). To assess the therapy efficacy, psychometric scales (CGI, MMSE, MoCA-test, МDRS, FAB, Clock Drawing Test, BNT, Word Recall test, delayed reproduction of 10 words, naming digits in a direct and reverse order) were used at 0, 4, 10 and 26 weeks of the study. Antibodies to p75 neurotrophin receptor (NTR) were measured by ELISA in blood serum of 19 patients before cerebrolysin therapy and after 10 and 26 weeks of treatment. RESULTS AND CONCLUSION: The study showed that аMCI patients had an increased level of antibodies against P75NTR that was significantly decreased after 5.5 month of cerebrolysin treatment. Therefore, it can be a potential biomarker of long-term therapeutic effect of cerebrolysin treatment in aMCI patients. The modified fragment 155-164 of P75 NTR determined in the serum of patients can be an effective indicator for monitoring and predicting the efficacy of long-term neurotrophic therapy.

Changes in Plasma ß-NGF and Its Receptors Expression on Peripheral Blood Monocytes During Alzheimer's Disease Progression.

Alzheimer's disease (AD), the most common cause of dementia, is characterized by the deposition of extracellular amyloid-ß (Aß) plaques and intracellular neurofibrillary tangles, and by neuroinflammation. During the pathogenesis of AD, monocyte-macrophage lineage cells become increasingly ineffective in clearing Aß deposits, less able to differentiate, and shift toward pro-inflammatory processes. Beta-nerve growth factor (ß-NGF) and its receptors, TrKA and p75NTR, produce several biological responses, including cell apoptosis and survival, and inflammation. In the central nervous system, the involvement of these receptors in several critical hallmarks of AD is well known, but their role in circulating monocytes during the progression of dementia is unclear. We investigated the relationship between plasma ß-NGF concentration and TrkA/p75NTR receptor expression in monocytes of patients with mild cognitive impairment (MCI), mild AD, and severe AD. We observed that plasma ß-NGF concentration was increased with a higher expression of TrKA, but not of p75NTR, in monocytes from patients with MCI and mild AD, whereas ß-NGF concentration and TrKA expression were decreased and p75NTR expression was increased, associated with caspase 3-mediated apoptosis, in patients with severe AD. In our study, we show evidence of variation in plasmatic ß-NGF and monocytic TrkA/p75NTR receptor expression during the progression of dementia. These novel findings add evidence to support the hypothesis for the involvement of ß-NGF and its receptors on monocytes during AD progression.

Milk growth factors and expression of small intestinal growth factor receptors during the perinatal period in mice.

BACKGROUND: Growth factors (GFs) are milk bioactive components contributing to the regulation of neonatal small intestinal maturation, and their receptors on the small intestinal epithelium play essential roles in mediating the functions of GFs. There is limited data correlating milk GFs and their receptors in the neonatal small intestine during the perinatal period. METHODS: Small intestines of C57BL/6N mouse pups were collected at regular intervals during fetal life and up to postnatal day (PD) 60. Gene expression of GF receptors was determined by real-time qPCR. Milk GF concentrations up to PD21 were analyzed by enzyme-linked immunosorbent assay. RESULTS: The majority of GF receptors showed significantly greater expression in the fetus than in postnatal life, and a sharp decrease occurred from PD14 extending to PD60; solid food restriction (PD14 and PD18) did not affect this decrease. Concentrations of five detected milk GFs demonstrated that GFs and the corresponding small intestinal receptors exhibited different correlations, with only milk transforming growth factor ß1 (TGF-ß1) having a significant positive correlation with TGF-ß receptor 1 mRNA. CONCLUSION: Gene expression of small intestinal GF receptors is likely a process of neonatal intestinal maturation that is affected concurrently by milk GFs and additional endogenous factors.

Levels of three distinct p75 neurotrophin receptor forms found in human plasma are altered in type 2 diabetic patients.

AIMS/HYPOTHESIS: The p75 neurotrophin receptor (p75NTR) has been shown to appear in the plasma of diabetic rats, possibly indicating diabetic neuropathy. The aim of this study was to use a semi-quantitative assay for human plasma p75NTR to investigate whether this receptor is a marker of peripheral diabetic neuropathy (DPN) and autonomic cardiovascular neuropathy (CAN) in type 2 diabetic patients. SUBJECTS AND METHODS: Eighty type 2 diabetic patients and 25 controls without diabetes were analysed for p75NTR immunoreactivity by western blot analysis. DPN was assessed using the Neuropathy Disability Score (NDS). Cardiovascular autonomic function was detected using a standardised analysis of heart rate variability. RESULTS: Three distinct p75NTR signals were detectable in human plasma at approximately 75, approximately 51 and approximately 24 kDa, representing the full length receptor (FL) and its intracellular domain (ICD) and extracellular domain (ECD), respectively. Levels of total plasma p75NTR immunoreactivity in patients with type 2 diabetes were similar to those in controls. Type 2 diabetic patients had significantly higher plasma levels of ICD and lower levels of ECD. However, there were no correlations of total p75NTR immunoreactivity or ECD or ICD immunoreactivity with NDS or aspects of CAN. CONCLUSIONS/INTERPRETATION: Levels of the ECD of p75NTR are reduced and levels of the ICD are increased in the plasma of type 2 diabetic patients. None of the p75NTR subunits identified in human plasma seem to be a marker of peripheral or autonomic neuronal function in patients with type 2 diabetes.

Hypogonadism, quadriceps weakness, and exercise intolerance in chronic obstructive pulmonary disease.

RATIONALE: Circulating levels of testosterone and gonadotrophins of patients with chronic obstructive pulmonary disease (COPD) have never been compared with those of elderly men with normal pulmonary function. Moreover, the relationship of hypogonadism with quadriceps muscle weakness and exercise intolerance has been studied scarcely in men with COPD. OBJECTIVES: To compare circulating levels of hormones of the pituitary-gonadotrophic axis of men with COPD with those of age-matched control subjects. Moreover, to study the relationship of hypogonadism with quadriceps muscle force, 6-min walking distance, and systemic markers of inflammation in the patients. METHODS AND MEASUREMENTS: Circulating levels of follicle-stimulating hormone, luteinizing hormone, testosterone, and sex hormone-binding globulin were determined, and free testosterone was calculated in 78 patients (FEV1: 44 +/- 17% of the predicted values) and 21 control subjects. Moreover, quadriceps muscle force, 6-min walking distance, number of pack-yr, and systemic inflammation were determined. MAIN RESULTS: Follicle-stimulating hormone and luteinizing hormone were higher in the patients, whereas testosterone was lower (p < or = 0.05). The latter finding was also present in 48 non-steroid-using patients with normal blood gases. Low androgen status was significantly related to quadriceps muscle weakness (r = 0.48) and C-reactive protein (r = -0.39) in the patients, but not to exercise intolerance, the number of pack-yr, or increased circulating levels of interleukin 8 or soluble receptors of tumor necrosis factor alpha. CONCLUSIONS: In contrast to exercise intolerance, quadriceps muscle weakness is related to low circulating levels of testosterone in men with COPD.

The p75 neurotrophin receptor appears in plasma in diabetic rats-characterisation of a potential early test for neuropathy.

AIMS/HYPOTHESIS: This study tested the premise that immunoreactivity representing the p75 neurotrophin receptor (p75(NTR)) appears in plasma of diabetic rats in association with the early stages of neuronal dysfunction or damage. We also examined whether treatment beneficial to neuropathy might reduce the p75(NTR) immunoreactivity. METHODS: Plasma proteins were fractionated by SDS-PAGE and immunoblots exposed to p75(NTR) antibody, using receptor protein from cultured PC12 cells as an external standard. Rats were made diabetic with streptozotocin for various periods and exsanguinated. Plasma glucose, HbA(1)c and plasma proteins were determined. We also studied plasma samples from diabetic mice lacking the gene coding for p75(NTR), as well as the effect of sciatic nerve crush on healthy male Wistar rats. RESULTS: Plasma p75(NTR) immunoreactivity began to exceed normal levels at 8 weeks after induction of diabetes, and was significantly raised at 10 (p<0.05) and 12 weeks (p<0.001). Treatment between 8 and 12 weeks with insulin, fidarestat (an aldose reductase inhibitor), nerve growth factor and neurotrophin 3 all normalised the plasma p75(NTR) immunoreactivity. Plasma from p75(NTR) (-/-) mice contained no such immunoreactivity, though it was present in plasma from wild-type mice. Following nerve crush, p75(NTR) immunoreactivity appeared in plasma of non-diabetic mice, indicating that this can be a result of nerve trauma. CONCLUSIONS/INTERPRETATION: These observations suggest that plasma p75(NTR) immunoreactivity may serve as an early indicator of neuronal dysfunction or damage in diabetes. The time course of its appearance relates well to that of early neuropathy and its response to interventions that are neuroprotective suggests that it might mirror neurological status.