Deletion of calcineurin from astrocytes reproduces proteome signature of Alzheimer’s disease and epilepsy and predisposes to seizures

ABSTRACTIn astrocytes, calcineurin (CaN) is involved in neuroinflammation and gliosis, while its role in healthy CNS or in early neuro-pathogenesis is poorly understood. Here we report that in astroglial CaN KO (ACN-KO) mice, at one month of age, proteome is deranged in hippocampus and cerebellum. Bioinformatic analysis reveals association with Alzheimer’s disease (AD) and epilepsy. We found significant overlap with the proteome of an AD mouse model and of human subjects with drug-resistant epilepsy. In Barnes maze ACN-KO mice learned the task but adopted serial search strategy. Strikingly, from five months of age ACN-KO mice develop spontaneous seizures with an inflammatory signature of epileptic brains. These results suggest that astroglial CaN KO impairs hippocampal connectivity, produces proteome features of neurological disorders and predisposes mice to seizures. We suggest that astroglial CaN may serve as a novel Ca2+-sensitive switch which regulates protein expression and homeostasis in the CNS.

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Isovitexin modulates autophagy in Alzheimer’s disease via miR-107 signalling

Translational Neuroscience ◽

10.1515/tnsci-2020-0109 ◽

2020 ◽

Vol 11 (1) ◽

pp. 391-401

Author(s):

Jiang Cheng ◽

Guowei Wang ◽

Na Zhang ◽

Fang Li ◽

Lina Shi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Memory Loss ◽

The Elderly ◽

Tnf Α ◽

Autophagic Process ◽

Molecular Signals ◽

Ad Mouse Model ◽

Mtor Signalling

AbstractBackground:Alzheimer’s disease (AD) is an ultimately fatal, degenerative brain disease in the elderly people. In the current work, we assessed the defensive capability of isovitexin (IVX) through an intracerebroventricular injection of streptozotocin (STZ)-induced AD mouse model.Methods:Mice were separated into four cohorts: sham-operated control mice; STZ-intoxicated Alzheimer’s mice; IVX cohort, IVX + STZ; and Ant-107 cohort, antagomiR-107 + IVX/STZ as in the IVX cohort.Results:The outcomes indicated that IVX administration ameliorated spatial memory loss and blunted a cascade of neuro-noxious episodes – including increased amyloid-beta (Aβ) and degraded myelin basic protein burden, neuroinflammation (represented by elevated caspase-1, TNF-α and IL-6 levels) and autophagic dysfunction (represented by altered LC3-II, Atg7 and beclin-1 expressions) – via the inhibition of PI3K/Akt/mTOR signalling axis. We considered the question of whether the epigenetic role of microRNA-107 (miR-107) has any impact on these events, by using antagomiR-107.Conclusion:This probing underscored that miR-107 could be a pivotal regulatory button in the activation of molecular signals linked with the beneficial autophagic process and anti-inflammatory activities in relation to IVX treatment. Hence, this report exemplifies that IVX could guard against Aβ toxicity and serve as an effectual treatment for patients afflicted with AD.

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Fingolimod Rescues Memory and Improves Pathological Hallmarks in the 3xTg-AD Model of Alzheimer’s Disease

Molecular Neurobiology ◽

10.1007/s12035-021-02613-5 ◽

2022 ◽

Author(s):

Steven G. Fagan ◽

Sibylle Bechet ◽

Kumlesh K. Dev

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Biochemical Analysis ◽

Spatial Working Memory ◽

Cell Number ◽

Model Of Alzheimer’S Disease ◽

Candidate Drug ◽

Inflammatory Processes ◽

The Brain ◽

Ad Mouse Model

AbstractTherapeutic strategies for Alzheimer’s disease (AD) have largely focused on the regulation of amyloid pathology while those targeting tau pathology, and inflammatory mechanisms are less explored. In this regard, drugs with multimodal and concurrent targeting of Aβ, tau, and inflammatory processes may offer advantages. Here, we investigate one such candidate drug in the triple transgenic 3xTg-AD mouse model of AD, namely the disease-modifying oral neuroimmunomodulatory therapeutic used in patients with multiple sclerosis, called fingolimod. In this study, administration of fingolimod was initiated after behavioral symptoms are known to emerge, at 6 months of age. Treatment continued to 12 months when behavioral tests were performed and thereafter histological and biochemical analysis was conducted on postmortem tissue. The results demonstrate that fingolimod reverses deficits in spatial working memory at 8 and 12 months of age as measured by novel object location and Morris water maze tests. Inflammation in the brain is alleviated as demonstrated by reduced Iba1-positive and CD3-positive cell number, less ramified microglial morphology, and improved cytokine profile. Finally, treatment with fingolimod was shown to reduce phosphorylated tau and APP levels in the hippocampus and cortex. These results highlight the potential of fingolimod as a multimodal therapeutic for the treatment of AD.

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Profiling Basal Forebrain Cholinergic Neurons Reveals a Molecular Basis for Vulnerability Within the Ts65Dn Model of Down Syndrome and Alzheimer’s Disease

10.21203/rs.3.rs-88218/v1 ◽

2020 ◽

Author(s):

Melissa J. Alldred ◽

Sai C. Penikalapati ◽

Sang Han Lee ◽

Adriana Heguy ◽

Panos Roussos ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Down Syndrome ◽

Basal Forebrain ◽

Differentially Expressed Gene ◽

Cholinergic Neurons ◽

Bioinformatic Analysis ◽

Selective Vulnerability ◽

Neuronal Population ◽

Single Population

Abstract Background: Basal forebrain cholinergic neuron (BFCN) degeneration is a hallmark of Down syndrome (DS) and Alzheimer’s disease (AD). Current therapeutics have been unsuccessful in slowing disease progression, likely due to complex pathological interactions and dysregulated pathways that are poorly understood. The Ts65Dn trisomic mouse model recapitulates both cognitive and morphological deficits of DS and AD, including BFCN degeneration. Methods: We utilized Ts65Dn mice to understand mechanisms underlying BFCN degeneration to identify novel targets for therapeutic intervention. We performed high-throughput, single population RNA sequencing (RNA-seq) to interrogate transcriptomic changes within medial septal nucleus (MSN) BFCNs, using laser capture microdissection to individually isolate ~500 choline acetyltransferase-immunopositive neurons in Ts65Dn and normal disomic (2N) mice at 6 months of age (MO). Results: Ts65Dn mice had unique MSN BFCNs transcriptomic profiles at ~6 MO clearly differentiating them from 2N mice. Leveraging Ingenuity Pathway Analysis and KEGG analysis, we linked differentially expressed gene (DEG) changes within MSN BFCNs to several canonical pathways and aberrant physiological functions. The dysregulated transcriptomic profile of trisomic BFCNs provides key information underscoring selective vulnerability within the septohippocampal circuit. Conclusions: We propose both expected and novel therapeutic targets for DS and AD, including specific DEGs within cholinergic, glutamate, GABAergic, and neurotrophin pathways, as well as select targets for repairing oxidative phosphorylation status in neurons. We demonstrate and validate an interrogative quantitative bioinformatic analysis of a key dysregulated neuronal population linking single population transcript changes to an established pathological hallmark associated with cognitive decline for therapeutic development in human DS and AD.

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Circuitry and Synaptic Dysfunction in Alzheimer’s Disease: A New Tau Hypothesis

Neural Plasticity ◽

10.1155/2020/2960343 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Siddhartha Mondragón-Rodríguez ◽

Humberto Salgado-Burgos ◽

Fernando Peña-Ortega

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Network Connectivity ◽

Aspartate Receptor ◽

Potential Biomarker ◽

Prodromal Ad ◽

Brain Circuit ◽

New Evidence ◽

Ad Mouse Model

For more than five decades, the field of Alzheimer’s disease (AD) has focused on two main hypotheses positing amyloid-beta (Aβ) and Tau phosphorylation (pTau) as key pathogenic mediators. In line with these canonical hypotheses, several groups around the world have shown that the synaptotoxicity in AD depends mainly on the increase in pTau levels. Confronting this leading hypothesis, a few years ago, we reported that the increase in phosphorylation levels of dendritic Tau, at its microtubule domain (MD), acts as a neuroprotective mechanism that prevents N-methyl-D-aspartate receptor (NMDAr) overexcitation, which allowed us to propose that Tau protein phosphorylated near MD sites is involved in neuroprotection, rather than in neurodegeneration. Further supporting this alternative role of pTau, we have recently shown that early increases in pTau close to MD sites prevent hippocampal circuit overexcitation in a transgenic AD mouse model. Here, we will synthesize this new evidence that confronts the leading Tau-based AD hypothesis and discuss the role of pTau modulating neural circuits and network connectivity. Additionally, we will briefly address the role of brain circuit alterations as a potential biomarker for detecting the prodromal AD stage.

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COMPLEMENT CONTRIBUTES TO ALZHEIMER’S DISEASE-INDUCED SYNAPSE DECLINE IN THE MURINE RETINA

Innovation in Aging ◽

10.1093/geroni/igz038.3506 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S967-S967

Author(s):

Fenge Li ◽

Danye Jiang ◽

Melanie Samuel

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Horizontal Cell ◽

Brain Dysfunction ◽

Cell Integrity ◽

Rt Pcr ◽

Aged Patients ◽

Complement Component C3 ◽

Cell Processes ◽

Ad Mouse Model

Abstract Alzheimer's disease (AD) is among the most debilitating form of cognitive impairment in aged patients. Synapse deficits are thought to be a central trigger of neural miswiring and brain dysfunction in AD. However, the pathways that control synapse connectivity remain largely unknown. The retina is an easily accessible system with two distinct synapse layers and three cellular layers comprised of distinct neural types. In this study, we leveraged this system to assess synapse and cell integrity in the APPNLGF amyloid-beta AD mouse model. We showed that the expression of the complement component C3 is significantly increased in APPNLGF retina synapses, and that there is a significant decline of several synapse-associated markers by RT-PCR. These mice also display disorganized horizontal cell processes and visual function deficits. These results suggest that complement may drive AD-related changes in the synaptic and functional properties of the retina, which could serve as assessable preclinical biomarkers for AD. In ongoing studies, we are testing whether and how complement regulates synapse refinement and shapes retina synapse specificity in AD.

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Regional differences in Alzheimer’s disease pathology confound behavioural rescue after amyloid-β attenuation

Brain ◽

10.1093/brain/awz371 ◽

2019 ◽

Vol 143 (1) ◽

pp. 359-373 ◽

Cited By ~ 5

Author(s):

Christopher D Morrone ◽

Paolo Bazzigaluppi ◽

Tina L Beckett ◽

Mary E Hill ◽

Margaret M Koletar ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Cognitive Function ◽

Spatial Memory ◽

Regional Differences ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Barnes Maze ◽

Tau Pathology

Abstract Failure of Alzheimer’s disease clinical trials to improve or stabilize cognition has led to the need for a better understanding of the driving forces behind cognitive decline in the presence of active disease processes. To dissect contributions of individual pathologies to cognitive function, we used the TgF344-AD rat model, which recapitulates the salient hallmarks of Alzheimer’s disease pathology observed in patient populations (amyloid, tau inclusions, frank neuronal loss, and cognitive deficits). scyllo-Inositol treatment attenuated amyloid-β peptide in disease-bearing TgF344-AD rats, which rescued pattern separation in the novel object recognition task and executive function in the reversal learning phase of the Barnes maze. Interestingly, neither activities of daily living in the burrowing task nor spatial memory in the Barnes maze were rescued by attenuating amyloid-β peptide. To understand the pathological correlates leading to behavioural rescue, we examined the neuropathology and in vivo electrophysiological signature of the hippocampus. Amyloid-β peptide attenuation reduced hippocampal tau pathology and rescued adult hippocampal neurogenesis and neuronal function, via improvements in cross-frequency coupling between theta and gamma bands. To investigate mechanisms underlying the persistence of spatial memory deficits, we next examined neuropathology in the entorhinal cortex, a region whose input to the hippocampus is required for spatial memory. Reduction of amyloid-β peptide in the entorhinal cortex had no effect on entorhinal tau pathology or entorhinal-hippocampal neuronal network dysfunction, as measured by an impairment in hippocampal response to entorhinal stimulation. Thus, rescue or not of cognitive function is dependent on regional differences of amyloid-β, tau and neuronal network dysfunction, demonstrating the importance of staging disease in patients prior to enrolment in clinical trials. These results further emphasize the need for combination therapeutic approaches across disease progression.

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