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Neurodegeneration in Diabetes Mellitus
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Narsingh Verma, Smriti Rastogi
τ, a microtubule-associated protein, is moderately phosphorylated under physiological conditions, but its hyperphosphorylation reflects pathogenicity and is a major pathological hallmark of neurodegeneration. Phosphorylated τ exists in the two distinct cis and trans conformations. cis p- τ is neurotoxic and drives neurodegeneration. It is accumulated in cultured neurons upon oxidative stress as well as nutrition depletion. Tubulin-associated unit (τ) hyperphosphorylation (p- τ) and aggregation along with Aβ plaque formation are the most common pathological hallmarks of neurodegeneration that are also observable in diabetic patients.16–20 These are detectable in the cerebrospinal fluid of diabetes patients with no neurodegenerative-dependent mutation. τ hyperphosphorylation reflects the formation of neurofibrillary tangles.13, 16 Notably, a disrupted insulin signaling pathway and glucose metabolism can induce p- τ formation.21–23
Degenerative Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James A. Mastrianni, Elizabeth A. Harris
The incidence of DLB in monozygotic twins is discordant, indicating that environmental and/or epigenetic factors play a role in disease pathogenesis. However, risk factors for DLB have not been clearly identified to date. Most cases are sporadic and late onset, though familial cases have been reported. The heritable component of DLB has been estimated to be approximately 36% based on one genome-wide association study.29 Mutations in genes linked to other neurodegenerative disease have also been implicated in DLB, including: SNCA: encoding alpha-synuclein protein.ApoE: encoding apolipoprotein E.APP: encoding amyloid precursor protein.PSEN-1/PSEN-2: encoding presenilin.MAPT: encoding microtubule-associated protein tau.GBA: encoding glucocerebrosidase.CNTN1: encoding contactin 1 (J).
Biochemical Markers for Alzheimer Disease as Reflection of the Neuropathology in Cerebrospinal Fluid:
Published in Robert E. Becker, Ezio Giacobini, Alzheimer Disease, 2020
C. Bancher, H.M. Wisniewski, P.D. Mehta, K.S. Kim, I. Grundke-Iqbal, K. Iqbal
Tau is a microtubule-associated protein. Its function in normal neurons is to promote the assembly of tubulin subunits into microtubules (Weingarten et al. 1975). In PHF, tau is modified (Grundke-Iqbal et al. 1986b, 1988; Nieto et al. 1988). The exact nature and the full extent of the modification are not yet known, but it includes abnormal phosphorylation (Grundke-Iqbal et al. 1986b), possibly at multiple sites (Iqbal et al. 1989a), and other alterations that change tau’s biochemical properties and its susceptibility to proteases. It is probably such an altered site of the tau molecule that defines the epitope recognized by the monoclonal antibody Alz-50 (Wolozin et al. 1986; Ksiezak-Reding and Yen 1989).
Lactobacillus plantarum DP189 prevents cognitive dysfunction in D-galactose/AlCl3 induced mouse model of Alzheimer’s disease via modulating gut microbiota and PI3K/Akt/GSK-3β signaling pathway
Published in Nutritional Neuroscience, 2022
Xinping Song, Zijian Zhao, Yujuan Zhao, Zhiguo Wang, Chao Wang, Ge Yang, Shengyu Li
Microtubule-associated protein tau facilitates and regulates microtubule formation and stability, which plays a vital role in regular neuronal activity. The abnormal hyperphosphorylation prevents tau from binding to the microtubules and facilitates neurofibrillary tangles, one of the major histological hallmarks of AD [36]. A remarkably increased tau phosphorylation at Ser396/Ser404 was detected in the cerebrospinal fluid of AD patients [37]. The current immunohistochemical results implicated that DP189 administration decreases the protein expression of tau phosphorylation at Ser404 site in the cerebral cortex and the hippocampus of AD model mice. Some protein kinases and protein phosphatases are responsible for regulating tau phosphorylation; GSK-3β kinase plays a leading role in tau hyperphosphorylation. Its activity is commonly regulated by inhibiting the phosphorylation on Ser9, which was enhanced by Tyr216 [38,39]. Reportedly, transgenic mice overexpressing GSK-3β showed tau hyperphosphorylation and neurodegeneration [40]. Additionally, mice overexpressing GSK-3β significantly attenuated hippocampal degeneration and cognitive deficits under a tau knockout background [41]. PI3 K/Akt are signaling molecules upstream of GSK-3β. Previous studies indicated that the brains of AD patients have reduced levels of PI3 K p85 or p110, phosphorylated Akt at Ser473 site, and phosphorylated GSK-3β at Ser9 site [42,43]. Interestingly, the current results revealed that DP189 administration restrains the activation of GSK-3β and decreases the expression of GSK-3β protein via increased PI3 K/Akt activity.
Role of computational and structural biology in the development of small-molecule modulators of the spliceosome
Published in Expert Opinion on Drug Discovery, 2022
Riccardo Rozza, Pavel Janoš, Angelo Spinello, Alessandra Magistrato
Small-molecules targeting RNA have also been developed to tackle other diseases. For example, the gene encoding for the microtubule-associated protein tau (MAPT) can give rise to six isoforms of the tau protein. Alzheimer’s disease and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) have been associated with mutations in the regulatory pre-mRNA sequence of MAPT. These mutations, located 14 nts downstream of the exon 10 5’SS, alter the alternative splicing of MAPT pre-mRNA leading to the exon 10 inclusion and to an over-production of so-called 4 R tau isoform, which is aggregate-prone [112,113]. Small-molecule modulators, targeting the bulged adenosine (bulge-A) of the exon 10–intron RNA hairpin motif and thus inducing exon 10 skipping, have been identified [114,115]. NMR experiments and restrained MD simulations supplied a structural model for their binding to the MAPT RNA stem-mimic duplex, showing that these compounds stack in-between the GC base pairs surrounding the bulge-A and form H-bonds and/or stacking interactions with the neighboring bases. While the stacking interactions are necessary for the binding, the interaction with the surrounding bases is key for the sequence-specific targeting of bulge-A flanked by GC pairs. The most promising compound name as 9 in ref [114], when tested in a mouse-derived assay, showed activity in a μM range.
Role of exosomes and its emerging therapeutic applications in the pathophysiology of non-infectious diseases
Published in Biomarkers, 2022
Gauresh G. Shivji, Rajib Dhar, Arikketh Devi
Alzheimer’s diseases (AD) is caused due to the abnormal accumulation of amyloid-beta (Aβ) protein. The exosomes in the AD patients promote the function of these proteins thus leading to more pathological conditions. Aβ accumulation is one of the main reasons for AD pathogenesis. Amyloid precursor protein (APP) is a transmembrane protein and its cleavage leads to the formation of Aβ. Exosomes obtained from the neuronal cells of the AD patients showed the mis-folded protein Aβ in a soluble and toxic form, Aβ1–42. These proteins aggregate, forming amyloid plaques thus reducing the function of the neurons. One more protein involved in the pathogenesis of AD is tau. It is a neuronal microtubule-associated protein and also plays an important role in neurite growth and axonal transport and many more. These functions are done by site-specific phosphorylation and it is disrupted when the tau protein is hyper-phosphorylated by 3–20 folds at threonine 181 (pT181-tau) and serine 396 (p-S396-tau) (Crotti et al. 2019). Exosomes from neuronal cells of AD patients have elevated levels of hyper-phosphorylated tau protein. AD patients had higher amount of p-T181 at later stages and comparatively less in the early stages. Thus the exosomes can be of great potential for the detection of levels of pathogenesis of AD patients and also as a significant biomarker for the disease.