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Insulin Resistance as a Risk Factor for Alzheimer's Disease
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Miren Ettcheto, Amanda Cano, Elena Sanchez-Lopez, Carme Auladell, Jaume Folch, Antoni Camins
In this way, PTP1B also regulates leptin signalling. Disturbances in this pathway, especially in the hippocampus, not only have been described in AD brains but also have been associated with Aβ oligomers, Tau phosphorylation in neurons and cognition and memory decline (94). Another important pathway in which PTP1B has been involved is the regulation of the brain derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) receptor (94). BDNF/TrkB have been related to synaptic development and evidence indicates that also plays a significant role in the synaptic plasticity (93). In this context, it has been reported that PTP1B overexpression reduces TrkB phosphorylation and, in consequence, the activation of downstream signalling pathway, such as the central BDNF. By contrast, its inhibition has been demonstrated to enhance TrKB signalling and improve memory in mice, thus, supporting the role of PTP1B in neuronal survival, morphogenesis and plasticity (93). Therefore, the inhibition of PTP1B represents a key target involved in the modulation of cognitive process.
Fetal Exposure to Mother’s Distress
Published in Rosa Maria Quatraro, Pietro Grussu, Handbook of Perinatal Clinical Psychology, 2020
Catherine Monk, Sophie Foss, Preeya Desai, Vivette Glover
Some of the transmission of risk, and likely some of the differences in outcome are due to differences in different genetic vulnerabilities of the children themselves. Qiu et al. (2017) have shown that the effects of both prenatal maternal depressive symptoms, and the effect of socioeconomic status, on neonatal brain development, are modulated by genetic risk. They conclude that their findings suggest gene-environment interdependence in the fetal development of brain regions implicated in cognitive-emotional function, and that candidate biological mechanisms involve a range of brain region-specific signaling pathways that converge on common processes of synaptic development.
Inorganic Chemical Pollutants
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
Deregulation of synaptic development and function has been implicated in the pathophysiology of neurodegenerative disorders and mental diseases. A neurotrophin that has an important function in neuronal and synaptic development is brain-derived neurotrophic factor (BDNF). Stansfield et al.347 examined the effects of lead (Pb2+) exposure on BDNF-tropomyosin-related kinase B (TrkB) signaling during the period of synaptogenesis in cultured neurons derived from embryonic rat hippocampi. They show that Pb2+ exposure decreases BDNF gene and protein expression, and it may also alter the transport of BDNF vesicles to sites of release by altering Huntington phosphorylation and protein levels. Combined, these effects of Pb2+ resulted in decreased concentrations of extracellular mature BDNF (mBDNF). The effect of Pb2+ on BDNF gene expression was associated with a specific decrease in calcium-sensitive exon IV transcript levels and reduced phosphorylation and protein expression of the transcriptional repressor methyl-CpG-binding protein (MeCP2). TrkB protein levels and the autophosphorylation at tyrosine 816 were significantly decreased by Pb2+ exposure with a concomitant increase in p75 neurotrophin receptor (p75NTR) levels and altered TrkB-p75NTR colocalization. Finally, phosphorylation of Synapsin I, a presynaptic target of BDNF-TrkB signaling, was significantly decreased by Pb2+ exposure with no effect on total Synapsin I protein levels. This effect of Pb2+ exposure on Synapsin I phosphorylation may help explain the impairment in vesicular release documented by Stansfield et al.347 previously. Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release.
Abnormal larval neuromuscular junction morphology and physiology in Drosophila prickle isoform mutants with known axonal transport defects and adult seizure behavior
Published in Journal of Neurogenetics, 2022
Atsushi Ueda, Tristan C. D. G. O’Harrow, Xiaomin Xing, Salleh Ehaideb, J. Robert Manak, Chun-Fang Wu
It is evident that the Drosophila larval neuromuscular preparation will remain as a highly relevant model to investigate the complex role of Prickle in neural development and function. It is known that pk mutations confer a spectrum of neurological phenotypes, most likely through interactions with a variety of synaptic proteins. Immunohistochemical and co-immunoprecipitation evidence indicates that mouse PRICKLE1 protein is physically associated with the protein SYNAPSIN I (Paemka et al., 2013), a major synaptic phosphoprotein, and that in the Drosophila larval NMJ transgenic Pk also co-localizes with Synapsin (Paemka et al., 2013). Drosophila Synapsin is known to influence synaptic development, synaptic vesicle formation, and transmitter release (Vasin et al., 2014). It will be important to examine whether interaction between Synapsin and Prickle plays a role in NMJ morphology and physiology. Notably, in addition to epilepsy, a link has been implicated between human PRICKLE mutations and autism (Sowers et al., 2013; Todd & Bassuk, 2018), which may involve disrupted physical association between PRICKLE1 and SYNAPSIN I (Paemka et al., 2013).
Using Behavioral Approaches to Assess Memory, Imitation and Motor Performance in Children with Angelman Syndrome: Results of a Pilot Study
Published in Developmental Neurorehabilitation, 2019
Mouse models of AS have been generated that contain a mutation or a deletion of the maternal Ube-3A gene.37 Due to the availability of these mouse models, it has been possible to closely study AS-specific aspects of learning and memory and identify related abnormalities in synaptic development and function. At a behavioral level, Ube3a mutant mice show deficits in associative learning (conditioned fear response), hippocampal long-term potentiation (which is related to formation of memories), motor performance, and context-dependent memory.38 In fact, it is the loss of hippocampal long-term potentiation that is hypothesized to give rise to learning impairments in individuals with AS.39 Current therapeutic approaches (both pharmacological and non-pharmacological) are geared toward ameliorating symptoms that are associated with AS and optimizing children’s development, by addressing seizures, sleep, motor and health-related problems, communication, learning and self-help skills.17,19,23,34,40–43 Another line of potential therapies aims to restore UBE-3A function by (a) activating the silent copy of the paternal UBE-3A allele; (b) insertion of the UBE-3A gene into neurons; or (c) normalizing pathways that are disrupted by the lack of UBE-3A.3,44 To date, clinical trials to evaluate therapeutic compounds for use in humans with AS have yielded interesting and at times promising results but no major breakthroughs.
Vitamin A and vitamin D deficiencies exacerbate symptoms in children with autism spectrum disorders
Published in Nutritional Neuroscience, 2019
Min Guo, Jiang Zhu, Ting Yang, Xi Lai, Yuxi Lei, Jie Chen, Tingyu Li
The occurrence of ASD is associated with abnormal excitatory synapse development.46 Neuronal homeostatic synaptic plasticity mediated by retinoic acid may be damaged due to excessive UBE3A dosage, resulting in ASD phenotypes.47 VD takes part in synaptic transmission that is related to hippocampal gene expression microarrays identified pathways and modulates cognitive function.48 So VAD and VDD may affect synaptic development including concurrent formation, elimination/pruning, and so on. Accumulating evidence suggests immune system dysfunction in ASD may be correlated with the severity of behavioral impairment and other developmental outcomes. In the cytokines analyzed, interleukin (IL)-1beta, IL-6, IL-8, interferon-gamma, eotaxin, and monocyte chemotactic protein-1 in ASD patients were significantly higher than those in control group.49 VA and VD co-deficiency reduced antibody responses in the respiratory tract, suggesting the important function of the two vitamins in immunoregulation.44 In conclusion, the influence imposed on autistic children’s symptoms by VA and VD co-deficiency may be pertaining to impairment of synaptic or immune function.