Co-Localization of Reelin and Proteolytic AβPP Fragments in Hippocampal Plaques in Aged Wild-Type Mice

Doehner, Jana; Madhusudan, Amrita; Konietzko, Uwe; Fritschy, Jean‐Marc; Knuesel, Irène

doi:10.3233/jad-2010-1333

Cited by 38 publications

(47 citation statements)

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“…Given that we found that they do not stain with Thioflavin S or with Hylite-AF488, and that Aβ-staining is a mistake due to the presence of the contaminant IgM, we conclude that there is no deposition of Aβ in these granular structures. It should be noted that Doehner et al (2010) reported that these granules stained with Thioflavin S, but we did not observe this positivity either in granules from SAMP8 mice or in those from APP/PS1 mice. In the latter, amyloid plaques were used as a positive control for Thioflavin S staining.…”

Section: Discussioncontrasting

confidence: 90%

Presence of a neo-epitope and absence of amyloid beta and tau protein in degenerative hippocampal granules of aged mice

Manich

Valle

Cabezón

et al. 2013

AGE

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Clustered pathological granules related to a degenerative process appear and increase progressively with age in the hippocampus of numerous mouse strains. We describe herein the presence of a neoepitope of carbohydrate nature in these granules, which is not present in other brain areas and thus constitutes a new marker of these degenerative structures. We also found that this epitope is recognised by a contaminant IgM present in several antibodies obtained from mouse ascites and from both mouse and rabbit sera. These findings entail the need to revise the high number of components that are thought to be present in the granules, such as the controversial β-amyloid peptides described in the granules of senescence-accelerated mouse prone-8 (SAMP8) mice. Characterisation of the composition of SAMP8 granules, taking into account the presence of the neo-epitope and the contaminant IgM, showed that granules do not contain either β-amyloid peptides or tau protein. The presence of the neo-epitope in the granules but not in other brain areas opens up a new direction in the study of the neurodegenerative processes associated with age. The SAMP8 strain, in which the progression of the granules is enhanced, may be a useful model for this purpose.

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Section: Discussioncontrasting

confidence: 90%

Presence of a neo-epitope and absence of amyloid beta and tau protein in degenerative hippocampal granules of aged mice

Manich

Valle

Cabezón

et al. 2013

AGE

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“…We have reported in aged rodents and nonhuman primates a pronounced reduction of Reelin-expressing interneurons and concomitant accumulation of Reelin in amyloid-like deposits, colocalizing with proteolytic APP fragments and associated with a reduction in basal forebrain projection neurons that selectively target Reelin-positive hippocampal interneurons Madhusudan et al, 2009;Doehner et al, 2010). The course and magnitude of the plaque load correlated with cognitive performance and was modulated by exacerbated inflammatory responses and genetic mutations favoring A␤ peptide production ).…”

Section: Introductionmentioning

confidence: 98%

“…A 15 min pepsin pretreatment (0.15 mg/ml in 0.2N HCl at 37°C) was applied to all the free-floating sections for epitope unmasking and reduction of nonspecific staining (Doehner et al, 2010). Sections were then briefly washed with PBS, pH 7.4, and processed for immunohistochemistry.…”

Section: Methodsmentioning

confidence: 99%

“…Animals were deeply anesthetized with Nembutal (40 mg/kg, i.p.). The tissue was perfusion fixed and processed as described previously Doehner et al, 2010). Random sampled serial sections were collected throughout the hippocampal formation starting at bregma level Ϫ0.85 to Ϫ3.5 and stored at Ϫ20°C in cryoprotectant solution until immunohistochemical or histological evaluations .…”

Section: Methodsmentioning

confidence: 99%

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Reduced Reelin Expression Accelerates Amyloid- Plaque Formation and Tau Pathology in Transgenic Alzheimer's Disease Mice

Kocherhans¹,

Madhusudan²,

Doehner³

et al. 2010

Journal of Neuroscience

108

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In addition to the fundamental role of the extracellular glycoprotein Reelin in neuronal development and adult synaptic plasticity, alterations in Reelin-mediated signaling have been suggested to contribute to neuronal dysfunction associated with Alzheimer's disease (AD). In vitro data revealed a biochemical link between Reelin-mediated signaling, Tau phosphorylation, and amyloid precursor protein (APP) processing. To directly address the role of Reelin in amyloid-␤ plaque and Tau pathology in vivo, we crossed heterozygous Reelin knock-out mice (reeler) with transgenic AD mice to investigate the temporal and spatial AD-like neuropathology. We demonstrate that a reduction in Reelin expression results in enhanced amyloidogenic APP processing, as indicated by the precocious production of amyloid-␤ peptides, the significant increase in number and size of amyloid-␤ plaques, as well as age-related aggravation of plaque pathology in double mutant compared with single AD mutant mice of both sexes. Numerous amyloid-␤ plaques accumulate in the hippocampal formation and neocortex of double mutants, precisely in layers with strongest Reelin expression and highest accumulation of Reelin plaques in aged wild-type mice. Moreover, concentric accumulations of phosphorylated Tau-positive neurons around amyloid-␤ plaques were evident in 15-month-old double versus single mutant mice. Silver stainings indicated the presence of neurofibrillary tangles, selectively associated with amyloid-␤ plaques and dystrophic neurites in the entorhinal cortex and hippocampus. Our findings suggest that age-related Reelin aggregation and concomitant reduction in Reelin-mediated signaling play a proximal role in synaptic dysfunction associated with amyloid-␤ deposition, sufficient to enhance Tau phosphorylation and tangle formation in the hippocampal formation in aged Reelin-deficient transgenic AD mice.

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“…Abnormal tau expression and hyperphosphorylation are common features in AD and DS (Khatoon et al, 1994;Oyama et al, 1994), causing abnormalities in the cytoskeleton. In addition, increases in tau expression have been reported in other mouse models of AD and aging (Manich et al, 2011;Doehner et al, 2010;Madhusudan et al, 2009). …”

Section: Accepted Manuscriptmentioning

confidence: 99%

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

García-Cerro

Rueda

Vidal

et al. 2017

Neurobiology of Disease

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The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dualspecificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology. Studies performed in vitro and in vivo in animal models overexpressing this gene have demonstrated that the DYRK1A gene also plays a crucial role in several neurodegenerative processes found in DS. The Ts65Dn (TS) mouse bears a partial triplication of several Hsa21 orthologous genes, including Dyrk1A, and replicates many DS-like abnormalities, including age-dependent cognitive decline, cholinergic neuron degeneration, increased levels of APP and Aβ, and tau hyperphosphorylation. To use a more direct approach to evaluate the role of the gene dosage of Dyrk1A on the neurodegenerative profile of this model, TS mice were crossed with Dyrk1A KO mice to obtain mice with a triplication of a segment of Mmu16 that includes this gene, mice that are trisomic for the same genes but only carry two copies of Dyrk1A, euploid mice with a normal Dyrk1A dosage, and CO animals with a single copy of Dyrk1A. Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aβ load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. Thus, the present study provides further support for the role of the Dyrk1A gene in several AD-like phenotypes found in TS mice and indicates that this gene could be a therapeutic target to treat AD in DS.

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Co-Localization of Reelin and Proteolytic AβPP Fragments in Hippocampal Plaques in Aged Wild-Type Mice

Cited by 38 publications

References 0 publications

Presence of a neo-epitope and absence of amyloid beta and tau protein in degenerative hippocampal granules of aged mice

Presence of a neo-epitope and absence of amyloid beta and tau protein in degenerative hippocampal granules of aged mice

Reduced Reelin Expression Accelerates Amyloid- Plaque Formation and Tau Pathology in Transgenic Alzheimer's Disease Mice

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

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