Region-Specific Differences in Amyloid Precursor Protein Expression in the Mouse Hippocampus

Turco, Domenico Del; Paul, Mandy H.; Schlaudraff, Jessica; Hick, Meike; Müller, Ulrike; Deller, Thomas

doi:10.3389/fnmol.2016.00134

Cited by 26 publications

(33 citation statements)

References 71 publications

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“…This study was however limited by the fact that APP expression was driven by an artificial prion promoter. Contrary to the long-held perception that APP is a ubiquitously expressed protein, regional and cell-type specific differences of endogenous APP expression, including a striking expression pattern in GABAergic interneurons, have been observed in the mouse hippocampus by us and others [28,31]. Moreover, GABAergic interneurons were found to be overrepresented in subpopulations of cells that secrete high levels of Aβ in a study that measured Aβ secretion with single-cell resolution from cultured human induced pluripotent stem cell-derived neurons and glia [16].…”

Section: Introductioncontrasting

confidence: 94%

Contribution of GABAergic interneurons to amyloid-β plaque pathology in an APP knock-in mouse model

Rice

Marcassa

Chrysidou

et al. 2020

Mol Neurodegeneration

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The amyloid-β (Aβ) peptide, the primary constituent of amyloid plaques found in Alzheimer's disease (AD) brains, is derived from sequential proteolytic processing of the Amyloid Precursor Protein (APP). However, the contribution of different cell types to Aβ deposition has not yet been examined in an in vivo, non-overexpression system. Here, we show that endogenous APP is highly expressed in a heterogeneous subset of GABAergic interneurons throughout various laminae of the hippocampus, suggesting that these cells may have a profound contribution to AD plaque pathology. We then characterized the laminar distribution of amyloid burden in the hippocampus of an APP knockin mouse model of AD. To examine the contribution of GABAergic interneurons to plaque pathology, we blocked Aβ production specifically in these cells using a cell type-specific knockout of BACE1. We found that during early stages of plaque deposition, interneurons contribute to approximately 30% of the total plaque load in the hippocampus. The greatest contribution to plaque load (75%) occurs in the stratum pyramidale of CA1, where plaques in human AD cases are most prevalent and where pyramidal cell bodies and synaptic boutons from perisomatic-targeting interneurons are located. These findings reveal a crucial role of GABAergic interneurons in the pathology of AD. Our study also highlights the necessity of using APP knock-in models to correctly evaluate the cellular contribution to amyloid burden since APP overexpressing transgenic models drive expression in cell types according to the promoter and integration site and not according to physiologically relevant expression mechanisms.

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Section: Introductioncontrasting

confidence: 94%

Contribution of GABAergic interneurons to amyloid-β plaque pathology in an APP knock-in mouse model

Rice

Marcassa

Chrysidou

et al. 2020

Mol Neurodegeneration

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“…We detected intraneuronal immunoreactive granules in the bilateral hippocampus and thalamus using 4G8 and 6E10 antibodies, but these deposits did not react with Aβ 40 or Aβ 42 antibodies that are specific for C-terminal epitopes; thus, the immunoreactivity revealed by 4G8 and 6E10 is not necessarily intraneuronal Aβ. Moreover, the intracellular deposits are found to widely distribute in neurons at different thalamic and hippocampal regions bilaterally, similar to the normal distribution of the APP protein (9). We suspect that this is likely because of the cross-reactivity with full length APP or other APP proteolytic fragments.…”

Section: Discussionmentioning

confidence: 51%

“…Briefly, citrate buffer pre-treated sections (10 minutes, 85°C) were treated with 3% of hydrogen peroxide for 15 minutes for quenching endogenous peroxidase activity, and blocked with 5% normal goat serum for 1 h at room temperature. Then, the sections were incubated with the following primary antibodies at 4°C overnight: mouse anti-Aβ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] (1:400 (43,55). Brain tissue from AD patients and AD transgenic mice were used as positive control.…”

Section: Immunochemistrymentioning

confidence: 99%

Neuronal loss without amyloid‐β deposits in the thalamus and hippocampus in the late period after middle cerebral artery occlusion in cynomolgus monkeys

Ouyang

Chen

et al. 2019

Brain Pathology

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Conflicting evidence exists regarding whether focal cerebral infarction contributes to cerebral amyloid-β (Aβ) deposition, as observed in Alzheimer's disease. In this study, we aimed to evaluate the presence of Aβ deposits in the ipsilateral thalamus and hippocampus 12 months post-stroke in non-human primates, whose brains are structurally and functionally similar to that of humans. Four young male cynomolgus monkeys were subjected to unilateral permanent middle cerebral artery occlusion (MCAO), and another four sham-operated monkeys served as controls. All monkeys underwent magnetic resonance imaging examination on post-operative day 7 to assess the location and size of the infarction. The numbers of neurons, astrocytes, microglia and the Aβ load in the non-affected thalamus and hippocampus ipsilaterally remote from infarct foci were examined immunohistochemically at sacrifice 12 months after operation. Thioflavin S and Congo Red stainings were used to identify amyloid deposits. Multiple Aβ antibodies recognizing both the N-terminal and Cterminal epitopes of Aβ peptides were used to avoid antibody cross-reactivity. Aβ levels in cerebrospinal fluid (CSF) and plasma were examined using enzyme-linked immunosorbent assay. The initial infarct was restricted to the left temporal, parietal, insular cortex and the subcortical white matter, while the thalamus and hippocampus remained intact. Of note, there were fewer neurons and more glia in the ipsilateral thalamus and hippocampus in the MCAO group at 12 months post-stroke compared to the control group (all P < 0.05). However, there was no sign of extracellular Aβ plaques in the thalamus or hippocampus. No statistically significant difference was found in CSF or plasma levels of Aβ 40 , Aβ 42 or the Aβ 40 /Aβ 42 ratio between the two groups (P > 0.05). These results suggest that significant secondary neuronal loss and reactive gliosis occur in the non-affected thalamus and hippocampus without Aβ deposits in the late period after MCAO in non-human primates.

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“…As an additional adaptive mechanism, cleavage of the protein is regulated by synaptic activity, affecting the balance between amyloidogenic and non-amyloidogenic pathways (Kamenetz et al, 2003 ; Cirrito et al, 2005 ). Intriguingly, APP is expressed and cleaved heterogeneously in different types of neurons and in astrocytes and in different brain areas, which might contribute to variable susceptibility to insults between brain regions and cell types (Del Turco et al, 2016 ; Liao et al, 2016 ). Activated by proinflammatory cytokines, astrocytes were shown both to contribute to Aß production as well as to stimulate the secretion of APPsα, suggesting a significant contribution of glia cells to production and cleavage of APP and a tight coupling between APP processing and the immune system (Zhao et al, 2011 ; Yang et al, 2015 ).…”

Section: App Structure Expression Trafficking Cleavage and Subcellmentioning

confidence: 99%

APP as a Protective Factor in Acute Neuronal Insults

Hefter

Draguhn

2017

Front. Mol. Neurosci.

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Despite its key role in the molecular pathology of Alzheimer’s disease (AD), the physiological function of amyloid precursor protein (APP) is unknown. Increasing evidence, however, points towards a neuroprotective role of this membrane protein in situations of metabolic stress. A key observation is the up-regulation of APP following acute (stroke, cardiac arrest) or chronic (cerebrovascular disease) hypoxic-ischemic conditions. While this mechanism may increase the risk or severity of AD, APP by itself or its soluble extracellular fragment APPsα can promote neuronal survival. Indeed, different animal models of acute hypoxia-ischemia, traumatic brain injury (TBI) and excitotoxicity have revealed protective effects of APP or APPsα. The underlying mechanisms involve APP-mediated regulation of calcium homeostasis via NMDA receptors (NMDAR), voltage-gated calcium channels (VGCC) or internal calcium stores. In addition, APP affects the expression of survival- or apoptosis-related genes as well as neurotrophic factors. In this review, we summarize the current understanding of the neuroprotective role of APP and APPsα and possible implications for future research and new therapeutic strategies.

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Region-Specific Differences in Amyloid Precursor Protein Expression in the Mouse Hippocampus

Cited by 26 publications

References 71 publications

Contribution of GABAergic interneurons to amyloid-β plaque pathology in an APP knock-in mouse model

Contribution of GABAergic interneurons to amyloid-β plaque pathology in an APP knock-in mouse model

Neuronal loss without amyloid‐β deposits in the thalamus and hippocampus in the late period after middle cerebral artery occlusion in cynomolgus monkeys

APP as a Protective Factor in Acute Neuronal Insults

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