Functional protection in J20/VLW mice: a model of non-demented with Alzheimer’s disease neuropathology

Brain ◽  
2021 ◽  
Author(s):  
Eva Dávila-Bouziguet ◽  
Arnau Casòliba-Melich ◽  
Georgina Targa-Fabra ◽  
Lorena Galera-López ◽  
Andrés Ozaita ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Amyloid Β ◽  
Rhythmic Activity ◽  
Hyperphosphorylated Tau ◽  
Field Potentials ◽  
Suitable Animal Model ◽  
Phosphorylation Pattern ◽  
Oscillatory Rhythms

Abstract Alzheimer’s disease comprises amyloid-β and hyperphosphorylated Tau accumulation, imbalanced neuronal activity, aberrant oscillatory rhythms, and cognitive deficits. Non-Demented with Alzheimer’s disease Neuropathology (NDAN) defines a novel clinical entity with amyloid-β and Tau pathologies but preserved cognition. The mechanisms underlying such neuroprotection remain undetermined and animal models of NDAN are currently unavailable. We demonstrate that J20/VLW mice (accumulating amyloid-β and hyperphosphorylated Tau) exhibit preserved hippocampal rhythmic activity and cognition, as opposed to J20 and VLW animals, which show significant alterations. Furthermore, we show that the overexpression of mutant human Tau in coexistence with amyloid-β accumulation renders a particular hyperphosphorylated Tau signature in hippocampal interneurons. The GABAergic septohippocampal pathway, responsible for hippocampal rhythmic activity, is preserved in J20/VLW mice, in contrast to single mutants. Our data highlight J20/VLW mice as a suitable animal model in which to explore the mechanisms driving cognitive preservation in NDAN. Moreover, they suggest that a differential Tau phosphorylation pattern in hippocampal interneurons prevents the loss of GABAergic septohippocampal innervation and alterations in local field potentials, thereby avoiding cognitive deficits.

scholarly journals Coexistence of amyloid-β and Tau hyperphosphorylation rescues cognitive and electrophysiological deficiencies in a mouse model of Alzheimer’s disease

2020 ◽  
Author(s):  
Eva Dávila-Bouziguet ◽  
Arnau Casòliba-Melich ◽  
Georgina Targa-Fabra ◽  
Lorena Galera-López ◽  
Andrés Ozaita ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Activity ◽  
Cognitive Deficits ◽  
Amyloid Β ◽  
Pyramidal Cells ◽  
Amyloid Β Peptide ◽  
Model Of Alzheimer’S Disease ◽  
Phosphorylation Pattern ◽  
Hippocampal Theta

AbstractAlzheimer’s disease hallmarks include amyloid-β peptide (Aβ) and hyperphosphorylated Tau (P-Tau), abnormalities in hippocampal oscillatory rhythms, imbalance of neuronal activity, and cognitive deficits. J20 and VLW mice, accumulating Aβ and P-Tau, respectively, show imbalanced neuronal activity and cognitive impairments. Here we analyzed mice simultaneously accumulating Aβ and P-Tau (J20/VLW). No changes in Aβ load or in P-Tau in pyramidal cells were observed in J20/VLW animals compared to respective single transgenic models. Conversely, the density of hippocampal interneurons accumulating pThr205 and pSer262 Tau was higher in J20/VLW than in VLW mice. The GABAergic septohippocampal (SH) connection specifically innervates hippocampal interneurons, modulating hippocampal electrophysiology. Contrarily to previous results showing an important reduction of GABAergic SH innervation in J20 and VLW mice, here we demonstrate that the GABAergic SH connection is preserved in J20/VLW animals. Furthermore, our findings indicate that hippocampal theta rhythms, markedly diminished in J20 and VLW mice, are partially rescued in J20/VLW animals. Moreover, the simultaneous presence of Aβ and P-Tau rescues Aβ-associated recognition memory deficits in J20/VLW mice. Altogether, these data suggest that a differential Tau phosphorylation pattern in hippocampal interneurons protects against loss of GABAergic SH innervation, preventing alterations in local field potentials and avoiding cognitive deficits.

scholarly journals Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease

2019 ◽  
Vol 22 (3) ◽  
pp. 401-412 ◽  
Author(s):  
Evandro F. Fang ◽  
Yujun Hou ◽  
Konstantinos Palikaras ◽  
Bryan A. Adriaanse ◽  
Jesse S. Kerr ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Amyloid Β ◽  
Tau Pathology

Cognitive enhancement of volatile oil from the stems of Schisandra chinensis Baill. in Alzheimer’s disease rats

2018 ◽  
Vol 96 (6) ◽  
pp. 550-555 ◽  
Author(s):  
Bingyou Yang ◽  
Bo Liu ◽  
Yan Liu ◽  
Hua Han ◽  
Haixue Kuang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Amyloid Β ◽  
Volatile Oil ◽  
Gas Chromatography Mass Spectrometry ◽  
Morris Water Maze Test ◽  
Schisandra Chinensis ◽  
Nerve Growth ◽  
Necrosis Factor

The volatile oil (VO), extracted from the stems of Schisandra chinensis Baill. (SCS), was separated and identified by gas chromatography – mass spectrometry. The study was devised to investigate the effects of VO on oxidative stress and cognitive deficits induced by amyloid-β (Aβ(1-42)). Alzheimer’s disease (AD) models were established by injecting Aβ(1-42) into the rat hippocampus and the effects of learning and memory were observed by a Morris water maze test, immunohistological alterations, and correlative indicators covering nerve growth (brain-derived neurotrophic factor, glial-cell-derived trophic factor, and nerve growth factor), interleukin 1β, tumor necrosis factor, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), glial fibrillary acidic protein (GFAP), and microglial CD11b in AD rats. And activities of SOD, MDA, and GSH-Px were ameliorated by VO. The neurotrophic factors GFAP and microglial CD11b were noticeably improved in histopathologic changes. These data suggested that VO from SCS had potential activities for the prevention and treatment of AD.

scholarly journals Propranolol reduces cognitive deficits, amyloid β levels, tau phosphorylation and insulin resistance in response to chronic corticosterone administration

2013 ◽  
Vol 16 (6) ◽  
pp. 1351-1360 ◽  
Author(s):  
Marta Dobarro ◽  
Lourdes Orejana ◽  
Norberto Aguirre ◽  
Maria J. Ramírez
Keyword(s):  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Glycogen Synthase ◽  
Amyloid Β ◽  
Tau Phosphorylation ◽  
Object Recognition Test ◽  
Adrenergic Antagonist ◽  
Propranolol Treatment

Abstract Chronic exposure to glucocorticoids might result not only in insulin resistance or cognitive deficits, but it is also considered as a risk factor for pathologies such as Alzheimer's disease. Propranolol is a β-adrenergic antagonist commonly used in the treatment of hypertension or acute anxiety. The effects of propranolol (5 mg/kg) have been tested in a model of chronic corticosterone administration (100 µg/ml, 4 wk) in drinking water. Corticosterone administration led to cognitive impairment in the novel object recognition test that was reversed by propranolol. Increased levels of Aβ in the hippocampus of corticosterone-treated mice were counteracted by propranolol treatment, purportedly through an increased IDE expression. Chronic corticosterone treatment induced responses characteristic of insulin resistance, as increased peripheral insulin levels, decreased activation of the insulin receptor (pIR) and decreased associated intracellular pathways (pAkt). These effects might be related to a decreased c-Jun N terminal kinase 1 expression. Again, propranolol was able to counteract all corticosterone-induced effects. One of the main kinases involved in tau phosphorylation, glycogen synthase kinase 3β (GSK3β), which is inactivated by phosphorylation by pAkt, was found to be decreased after corticosterone and increased after propranolol treatment. Concomitant changes in pTau expression were found. Overall, these data further strengthen the potential of propranolol as a therapeutic agent for pathologies associated with the interaction glucocorticoids-insulin resistance and the development of relevant cellular processes for Alzheimer's disease.

Chronic glucocorticoids consumption triggers and worsens experimental Alzheimer’s disease-like pathology by detrimental immune-modulations

2021 ◽  
Author(s):  
Geoffrey Canet ◽  
Charleine Zussy ◽  
Célia Hernandez ◽  
Nathalie Chevallier ◽  
Nicola Marchi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Functional Outcomes ◽  
Amyloid Β ◽  
Memory Deficits ◽  
Stressful Events ◽  
Main Risk Factor ◽  
Clinical Observations ◽  
The One

Introduction: Among the risk factors identified in the sporadic forms of Alzheimer’s disease (AD), environmental and lifestyle elements are of growing interest. Clinical observations suggest that stressful events can anticipate AD onset, while stress-related disorders can promote AD. Here, we tested the hypothesis that a chronic treatment with glucocorticoids, is sufficient to trigger or exacerbate AD molecular hallmarks. Methods: We first validated a rat model of experimental chronic glucocorticoids consumption (corticosterone in drinking water for 4 weeks). Then, to evaluate the consequences of chronic glucocorticoids consumption on the onset of amyloid-β (Aβ) toxicity, animals chronically treated with glucocorticoids were intracerebroventricularly injected with an oligomeric solution of Aβ25-35 (oAβ) (acute model of AD). We evaluated AD-related cognitive deficits and pathogenic mechanisms, with a special emphasis on neuroinflammatory markers. Results: Chronic corticosterone consumption caused the inhibition of the non-amyloidogenic pathways, the impairment of Aβ clearance processes and the induction of amyloidogenic pathways in the hippocampus. The principal enzymes involved in glucocorticoid receptor (GR) activation and Tau phosphorylation were upregulated. Importantly, the AD-like phenotype triggered by chronic corticosterone was analogous to the one caused by oAβ. These molecular commonalities across models were independent from inflammation, as chronic corticosterone was immunosuppressive while oAβ was pro-inflammatory. When chronic corticosterone consumption anticipated the induction of the oAβ pathology, we found a potentiation of neuroinflammatory processes associated with an exacerbation of synaptic and memory deficits but also an aggravation of AD-related hallmarks. Discussion/Conclusion: This study unravels new functional outcomes identifying chronic corticosterone consumption as a main risk factor for AD and suggests that glucocorticoid-based therapies should be prescribed with caution in populations with AD risk.

scholarly journals Elevated Norepinephrine Metabolism Gauges Alzheimer’s Disease-Related Pathology and Memory Decline

2021 ◽  
Vol 80 (2) ◽  
pp. 521-526
Author(s):  
Joost M. Riphagen ◽  
Maxime van Egroo ◽  
Heidi I.L. Jacobs
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dose Response ◽  
Time Trends ◽  
Amyloid Β ◽  
Hyperphosphorylated Tau ◽  
Memory Clinic ◽  
Memory Decline ◽  
Disease Biomarkers ◽  
Norepinephrine Metabolism

The noradrenergic (NE) locus coeruleus (LC) is vulnerable to hyperphosphorylated tau, and dysregulated NE-metabolism is linked to greater tau and disease progression. We investigated whether elevated NE-metabolism alone predicts memory decline or whether concomitant presence of tau and amyloid-β is required. Among 114 memory clinic participants, time trends (max. six years) showed dose-response declines in learning across groups with elevated NE-metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) with no, one, or two Alzheimer’s disease biomarkers; and no decline in the low MHPG group. Elevated MHPG is required and sufficient to detect learning declines, supporting a pathophysiologic model including the LC-NE system contributing to initial Alzheimer’s disease-related processes.

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