Faculty Opinions recommendation of A mouse model of amyloid beta oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo.

Alzheimer’s disease (AD) is a complex, age-related neurodegenerative disease that is the most common form of dementia. However, the cure for AD has not yet been founded. The accumulation of amyloid beta (Aβ) is considered to be a hallmark of AD. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), also known as beta secretase is the initiating enzyme in the amyloidogenic pathway. Blocking BACE1 could reduce the amount of Aβ, but this would also prohibit the other functions of BACE1 in brain physiological activity. SPONDIN1 (SPON1) is known to bind to the BACE1 binding site of the amyloid precursor protein (APP) and blocks the initiating amyloidogenesis. Here, we show the effect of SPON1 in Aβ reduction in vitro in neural cells and in an in vivo AD mouse model. We engineered mouse induced neural stem cells (iNSCs) to express Spon1. iNSCs harboring mouse Spon1 secreted SPON1 protein and reduced the quantity of Aβ when co-cultured with Aβ-secreting Neuro 2a cells. The human SPON1 gene itself also reduced Aβ in HEK 293T cells expressing the human APP transgene with AD-linked mutations through lentiviral-mediated delivery. We also demonstrated that injecting SPON1 reduced the amount of Aβ and ameliorated cognitive dysfunction and memory impairment in 5xFAD mice expressing human APP and PSEN1 transgenes with five AD-linked mutations.

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Modulation of CRMP2 via (S)-Lacosamide shows therapeutic promise but is ultimately ineffective in a mouse model of CLN6-Batten disease

Neuronal Signaling ◽

10.1042/ns20190001 ◽

2019 ◽

Vol 3 (2) ◽

Author(s):

Katherine A. White ◽

Jacob T. Cain ◽

Helen Magee ◽

Seul Ki Yeon ◽

Ki Duk Park ◽

...

Keyword(s):

Mouse Model ◽

Neurodegenerative Disorder ◽

Batten Disease ◽

Glial Activation ◽

Neuronal Cultures ◽

Term Survival ◽

Collapsin Response Mediator Protein ◽

Mediator Protein

Abstract CLN6-Batten disease is a rare neurodegenerative disorder with no cure, characterized by accumulation of lipofuscin in the lysosome, glial activation, and neuronal death. Here we test the therapeutic efficacy of modulating collapsin response mediator protein 2 (CRMP2) activity via S-N-benzy-2-acetamido-3-methoxypropionamide ((S)-Lacosamide) in a mouse model of CLN6-Batten disease. Promisingly, mouse neuronal cultures as well as Cln6 patient fibroblasts treated with varying concentrations of (S)-Lacosamide showed positive restoration of lysosomal associated deficits. However, while acute in vivo treatment enhanced glial activation in 3-month-old Cln6 mutant mice, chronic treatment over several months did not improve behavioral or long-term survival outcomes. Therefore, modulation of CRMP2 activity via (S)-Lacosamide alone is unlikely to be a viable therapeutic target for CLN6-Batten disease.

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O4-05-01: Intraneuronal accumulation of Aβ oligomers causes abnormal tau phosphorylation, glial activation and neuronal loss in transgenic mice with APP E693Δ mutation

Alzheimer s & Dementia ◽

10.1016/j.jalz.2010.05.488 ◽

2010 ◽

Vol 6 ◽

pp. S156-S157

Author(s):

Takami Tomiyama ◽

Tomohiro Umeda ◽

Naomi Sakama ◽

Mary P. Lambert ◽

William L. Klein ◽

...

Keyword(s):

Transgenic Mice ◽

Neuronal Loss ◽

Tau Phosphorylation ◽

Glial Activation ◽

Aβ Oligomers

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Amyloid Beta Peptide-Induced Cerebral Neuronal Loss Is Mediated By Caspase-3 In Vivo

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/63.3.255 ◽

2004 ◽

Vol 63 (3) ◽

pp. 255-261 ◽

Cited By ~ 42

Author(s):

Hiroshi Takuma ◽

Takami Tomiyama ◽

Keisuke Kuida ◽

Hiroshi Mori

Keyword(s):

Amyloid Beta ◽

Caspase 3 ◽

Neuronal Loss ◽

Amyloid Beta Peptide ◽

Beta Peptide

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Reducing miR485-3p ameliorates Alzheimer`s disease pathology by regulation of amyloid beta and neuro-inflammation

10.21203/rs.3.rs-19583/v1 ◽

2020 ◽

Author(s):

Han Seok Koh ◽

Hannah Jang ◽

SooKil Tae ◽

mi-sun Lee ◽

Jae-Woong Min ◽

...

Keyword(s):

Mouse Model ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Amyloid Β ◽

Neuronal Loss ◽

Precentral Gyrus ◽

Alzheimer Patient ◽

5Xfad Mice

Abstract Background Alzheimer`s disease (AD) is a progressive neurodegenerative disease worldwide. Accumulation of amyloid-β (Aβ), neurofibrillary tangles and neuroinflammation play the important neuro-pathology in patients with AD. miRNA is multifunctional and involved in physiological and pathological processes. Recently, microRNAs have been linked to neurodegenerative diseases. However, it is little known whether miRNA dysregulation contributes to AD pathology progression such as Aβ processing, phagocytosis and neuroinflammation. Here, we identify miR485-3p as a novel modulator of AD pathology in 5XFAD mice. Methods To study the role of miR485-3p in AD, we used in control or miR485-3p antisense oligonucleotides (miR485-3p ASO) injected 5XFAD mouse model. Changes of Aβ processing and clearance and inflammation were analyzed by biochemical method in vitro and in vivo. Result This study suggests that miR485-3p, a novel miRNA targeting SIRT1 may contribute to pathogenesis in an AD mouse. We found SIRT1 is significantly reduced in the precentral gyrus of Alzheimer patient`s and in 5XFAD mice. To determine whether the inhibition of miRNA 485-3p would affect AD pathology, we studied the effect of the antisense oligo in the brain of 5XFAD mice through direct intracerebral ventricular injection with miR485-3p ASO. We demonstrated that miR485-3p ASO significantly reduced Aβ plaque and amyloid biosynthetic enzyme. Importantly, the attenuation of Aβ plaques through miR485-3p ASO was mediated through Aβ phagocytic activity of glial cells, by which it can directly target CD36. MiR485-3p ASO also decreased inflammatory responses. Collectively, these responses inhibited neuronal loss caused by Aβ lead to improvements of cognitive impairment. Conclusion Our data provide evidence for the molecular mechanisms which underlie the miR485-3p ASO responses in an AD mouse model. These results suggest that attenuating miRNA 485-3p levels might represent a novel therapeutic approach in AD.

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Investigating in vivo the principles governing the spread of tau phosphorylation and amyloid-beta excitotoxicity

10.14264/uql.2017.150 ◽

2016 ◽

Author(s):

Sian Baker

Keyword(s):

Amyloid Beta ◽

Tau Phosphorylation

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Increased soluble amyloid-beta causes early aberrant brain network hypersynchronisation in a mature-onset mouse model of amyloidosis

10.1101/723981 ◽

2019 ◽

Author(s):

Inès R.H. Ben-Nejma ◽

Aneta J. Keliris ◽

Jasmijn Daans ◽

Peter Ponsaerts ◽

Marleen Verhoye ◽

...

Keyword(s):

Mouse Model ◽

Postnatal Development ◽

Amyloid Beta ◽

Resting State ◽

Ex Vivo ◽

Fold Increase ◽

Brain Network ◽

Resting State Networks ◽

The Impact

ABSTRACTBackgroundAlzheimer’s disease (AD) is the most common form of dementia in the elderly population. Currently, no effective cure is available for AD. According to the amyloid hypothesis, the accumulation and deposition of the amyloid-beta (Aβ) peptides plays a key role in AD pathology. Soluble Aβ (sAβ) oligomers were shown to be synaptotoxic and involved in pathological hypersynchronisation of brain resting-state networks in different transgenic developmental-onset mouse models of amyloidosis. However, the impact of protein overexpression during brain postnatal development may cause additional phenotypes unrelated to AD. To address this concern, we investigated sAβ effects on functional resting-state networks in transgenic mature-onset amyloidosis Tet-Off APP (TG) mice.MethodsTG mice and control littermates were raised on doxycycline (DOX) diet from 3d up to 3m of age to suppress transgenic Aβ production. Thereafter, longitudinal resting-state functional MRI was performed on a 9.4T MR-system starting from week 0 (3m old mice) up to 28w post DOX treatment. Ex vivo immunohistochemistry and ELISA analysis (additional mice cohort) was performed to address the development of amyloid pathology.ResultsFunctional Connectivity (FC) analysis demonstrated early abnormal hypersynchronisation in the TG mice compared to the controls at 8w post DOX treatment. This effect was observed particularly across regions of the default mode-like network, known to be affected in AD. Ex vivo analyses performed at this time point confirmed a 20-fold increase in total sAβ levels and the absence of Aβ plaques in the TG mice compared to the controls. On the contrary at week 28, TG mice showed an overall hypoconnectivity, coinciding with a widespread deposition of Aβ plaques in the brain.ConclusionsBy preventing developmental influence of APP and/or sAβ during brain postnatal development, we demonstrated FC abnormalities driven by sAβ synaptotoxicity on resting state neuronal networks in mature-induced TG mice. Thus, the Tet-Off APP mouse model could be a powerful tool while used as a mature-onset model to shed light into amyloidosis mechanisms in AD. Therefore, this inducible APP expression model used in combination with early non-invasive in vivo rsfMRI readout for sAβ synaptotoxicity sets the stage for future Aβ targeting preventative treatment studies.

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Microvessel occlusions alter amyloid-beta plaque morphology in a mouse model of Alzheimer’s disease

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x19889092 ◽

2019 ◽

Vol 40 (10) ◽

pp. 2115-2131

Author(s):

Yuying Zhang ◽

Evan D Bander ◽

Yurim Lee ◽

Celia Muoser ◽

Chris B Schaffer ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Amyloid Beta ◽

Multiphoton Microscopy ◽

Transient Increase ◽

Plaque Burden ◽

Plaque Morphology ◽

Model Of Alzheimer’S Disease

Vascular dysfunction is correlated to the incidence and severity of Alzheimer’s disease. In a mouse model of Alzheimer’s disease (APP/PS1) using in vivo, time-lapse, multiphoton microscopy, we found that occlusions of the microvasculature alter amyloid-beta (Aβ) plaques. We used several models of vascular injury that varied in severity. Femtosecond laser-induced occlusions in single capillaries generated a transient increase in small, cell-sized, Aβ deposits visualized with methoxy-X04, a label of fibrillar Aβ. After occlusions of penetrating arterioles, some plaques changed morphology, while others disappeared, and some new plaques appeared within a week after the lesion. Antibody labeling of Aβ revealed a transient increase in non-fibrillar Aβ one day after the occlusion that coincided with the disappearance of methoxy-X04-labeled plaques. Four days after the lesion, anti-Aβ labeling decreased and only remained in patches unlabeled by methoxy-X04 near microglia. Histology in two additional models, sparse embolic occlusions from intracarotid injections of beads and infarction from photothrombosis, demonstrated increased labeling intensity in plaques after injury. These results suggest that microvascular lesions can alter the deposition and clearance of Aβ and confirm that Aβ plaques are dynamic structures, complicating the interpretation of plaque burden as a marker of Alzheimer’s disease progression.

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