P2-022: Peripheral inflammation increases PKR, GSK3β, and tau phosphorylation in wild-type mice

Background: 3,4-Methylenedioxymethamphetamine (MDMA) is still one of the most consumed drugs by adolescents. Its abuse is related with cognitive impairment, which seems due to maladaptive plasticity and neural stress. In turn, new hypotheses suggest that Alzheimer’s disease (AD) may be promoted by neural stressors. Aims and methods: To test if there is an increase in vulnerability to AD after chronic MDMA consumption, we investigated the effects of this drug on recognition memory and its neurotoxic and neuroplastic effects in a transgenic mouse model of presymptomatic familiar AD (APP/PS1 dE9, Tg). Results: MDMA-treated animals showed recognition memory deficits, regardless of genotype, which were accompanied by changes in plasticity markers. Tg mice showed an impaired expression of Arc compared with wild-type animals, but exposure to MDMA induced an increase in the expression of this factor of the same percentage in both genotypes. However, the expression of c-fos, BDNF and p-CREB was not significantly altered by MDMA treatment in Tg mice. Although Tg mice had higher free choline levels than wild-type mice (about 123%), MDMA did not modify these levels in any case, ruling out any specific effect of this drug on the acetylcholine pathway. MDMA treatment significantly increased the presence of cortical amyloid plaques, as well as Aβ40, Aβ42 and secreted APPβ levels in Tg mice. These plaques were accompanied by increased tau phosphorylation (S199), which does not seem to occur via the canonic pathway involving AKT, CDK5 or GSK3β. Conclusions: The present results support previous evidences that MDMA can contribute to the amyloid cascade.

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Estrogens Inhibit Amyloid-β-Mediated Paired Helical Filament-Like Conformation of Tau Through Antioxidant Activity and miRNA 218 Regulation in hTau Mice

Journal of Alzheimer s Disease ◽

10.3233/jad-200707 ◽

2020 ◽

Vol 77 (3) ◽

pp. 1339-1351

Author(s):

Michela Guglielmotto ◽

Giusi Manassero ◽

Valeria Vasciaveo ◽

Marika Venezia ◽

Massimo Tabaton ◽

...

Keyword(s):

Antioxidant Activity ◽

Conformational Changes ◽

Amyloid Β ◽

Tau Phosphorylation ◽

Paired Helical Filament ◽

Wild Type ◽

Aβ Peptides ◽

Biological Sex ◽

Nanomolar Concentration ◽

Estradiol Levels

Background: The risk of developing Alzheimer’s disease as well as its progression and severity are known to be different in men and women, and cognitive decline is greater in women than in men at the same stage of disease and could be correlated at least in part on estradiol levels. Objective: In our work we found that biological sex influences the effect of amyloid-β42 (Aβ42) monomers on pathological tau conformational change. Methods: In this study we used transgenic mice expressing the wild-type human tau (hTau) which were subjected to intraventricular (ICV) injections of Aβ peptides in nanomolar concentration. Results: We found that Aβ42 produces pathological conformational changes and hyperphosphorylation of tau protein in male or ovariectomized female mice but not in control females. The treatment of ovariectomized females with estradiol replacement protects against the pathological conformation of tau and seems to be mediated by antioxidant activity as well as the ability to modulate the expression of miRNA 218 linked to tau phosphorylation. Conclusion: Our study indicates that factors as age, reproductive stage, hormone levels, and the interplay with other risk factors should be considered in women, in order to identify the best appropriate therapeutic approach in prevention of cognitive impairment.

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Tau phosphorylation and expression in (non)-neuronal cells expressing wild type of mutant (A692G and E693Q) amyloid precursor protein

Neurobiology of Aging ◽

10.1016/s0197-4580(00)82306-4 ◽

2000 ◽

Vol 21 ◽

pp. 113

Author(s):

Ann Julliams ◽

Inge Vanderhoeven ◽

Christine Van Broeckhoven

Keyword(s):

Amyloid Precursor Protein ◽

Neuronal Cells ◽

Tau Phosphorylation ◽

Precursor Protein ◽

Wild Type

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Extracellular Vesicles Isolated from Familial Alzheimer’s Disease Neuronal Cultures Induce Aberrant Tau Phosphorylation in the Wild-Type Mouse Brain

Journal of Alzheimer s Disease ◽

10.3233/jad-190656 ◽

2019 ◽

Vol 72 (2) ◽

pp. 575-585 ◽

Cited By ~ 10

Author(s):

Brent Aulston ◽

Qing Liu ◽

Michael Mante ◽

Jazmin Florio ◽

Robert A. Rissman ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Extracellular Vesicles ◽

Mouse Brain ◽

Wild Type Mouse ◽

Tau Phosphorylation ◽

Neuronal Cultures ◽

Wild Type ◽

Familial Alzheimer’S Disease ◽

In The Wild ◽

Familial Alzheimer's Disease

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SCN11A gene deletion causes sensorineural hearing loss by impairing the ribbon synapses and auditory nerves

BMC Neuroscience ◽

10.1186/s12868-021-00613-8 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Mian Zu ◽

Wei-Wei Guo ◽

Tao Cong ◽

Fei Ji ◽

Shi-Li Zhang ◽

...

Keyword(s):

Sodium Channels ◽

Hair Cells ◽

Gene Deletion ◽

Peripheral Inflammation ◽

Wild Type ◽

Nociceptive Neurons ◽

Quantitative Expression ◽

Ribbon Synapses ◽

Auditory Nerves

Abstract Background The SCN11A gene, encoded Nav1.9 TTX resistant sodium channels, is a main effector in peripheral inflammation related pain in nociceptive neurons. The role of SCN11A gene in the auditory system has not been well characterized. We therefore examined the expression of SCN11A in the murine cochlea, the morphological and physiological features of Nav1.9 knockout (KO) ICR mice. Results Nav1.9 expression was found in the primary afferent endings beneath the inner hair cells (IHCs). The relative quantitative expression of Nav1.9 mRNA in modiolus of wild-type (WT) mice remains unchanged from P0 to P60. The number of presynaptic CtBP2 puncta in Nav1.9 KO mice was significantly lower than WT. In addition, the number of SGNs in Nav1.9 KO mice was also less than WT in the basal turn, but not in the apical and middle turns. There was no lesion in the somas and stereocilia of hair cells in Nav1.9 KO mice. Furthermore, Nav1.9 KO mice showed higher and progressive elevated ABR threshold at 16 kHz, and a significant increase in CAP thresholds. Conclusions These data suggest a role of Nav1.9 in regulating the function of ribbon synapses and the auditory nerves. The impairment induced by Nav1.9 gene deletion mimics the characters of cochlear synaptopathy.

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