Aβ Deposition Is Associated with Neuropil Changes, but not with Overt Neuronal Loss in the Human Amyloid Precursor Protein V717F (PDAPP) Transgenic Mouse

Irizarry, Michael C.; Soriano, Ferdie; McNamara, Megan J.; Page, Kyle S.; Schenk, Dale; Games, Dora; Hyman, Bradley T.

doi:10.1523/jneurosci.17-18-07053.1997

Cited by 475 publications

(283 citation statements)

References 48 publications

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“…Only after inflicting neuronal damage to the locus coeruleus, a significant difference between the two animal groups could be observed. A possible explanation for preserved cerebral glucose metabolism in Tg mice compared with Wt mice may be the lack of a global neuronal loss in the brains of APP and APP/PS1 mouse models, despite their extensive amyloid plaque pathology at the age of investigation (Irizarry et al, 1997;Takeuchi et al, 2000).…”

Section: Supplementary Discussionmentioning

confidence: 99%

Imaging microglial activation and glucose consumption in a mouse model of Alzheimer's disease

Rapic

Backes

Viel

et al. 2013

Neurobiology of Aging

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Abstract. In Alzheimer´s disease (AD), persistent microglial activation as sign of chronic neuroinflammation contributes to disease progression. Our study aimed to in vivo visualize and quantify microglial activation in 13-to 15-month-old AD mice using [ 11 C]-(R)-PK11195 and positron emission tomography (PET). We attempted to modulate neuroinflammation by subjecting the animals to an anti-inflammatory treatment with pioglitazone (5-weeks' treatment, 5-week wash-out period).[ 11 C]-(R)-PK11195 distribution volume values in AD mice were significantly higher compared with control mice after the wash-out period at 15 months, which was supported by immunohistochemistry data. However, [ 11 C]-(R)-PK11195 µPET could not demonstrate genotype-or treatment-dependent differences in the 13-to 14 month-old animals, suggesting that microglial activation in AD mice at this age and disease stage is too mild to be detected by this imaging method.Introduction. In AD, activated microglia are found in the direct vicinity of amyloid β (Aβ) plaques.

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Section: Supplementary Discussionmentioning

confidence: 99%

Imaging microglial activation and glucose consumption in a mouse model of Alzheimer's disease

Rapic

Backes

Viel

et al. 2013

Neurobiology of Aging

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“…41 In contrast, in a third mouse model with amyloid plaque formation, PD-APP mice, 42 significant amounts of diffuse amyloid, no neuronal loss, and only occasional microglial clustering around amyloid plaques were reported. 43,44 The observations from the APP23, PrP-APP, and PD-APP transgenic mouse models suggest that amyloid-associated activated microglia may be important for the neurodegeneration in these mice and perhaps in AD.…”

Section: Discussionmentioning

confidence: 99%

Association of Microglia with Amyloid Plaques in Brains of APP23 Transgenic Mice

Stalder¹,

Phinney²,

Probst³

et al. 1999

The American Journal of Pathology

304

201

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Microglia are a key component of the inflammatory response in the brain and are associated with senile plaques in Alzheimer's disease (AD). Although there is evidence that microglial activation is important for the pathogenesis of AD , the role of microglia in cerebral amyloidosis remains obscure. The present study was undertaken to investigate the relationship between ␤-amyloid deposition and microglia activation in APP23 transgenic mice which express human mutated amyloid-␤ precursor protein (␤PP) under the control of a neuron-specific promoter element. Light microscopic analysis revealed that the majority of the amyloid plaques in neocortex and hippocampus of 14-to 18-month-old APP23 mice are congophilic and associated with clusters of hypertrophic microglia with intensely stained Mac-1-and phosphotyrosinepositive processes. No association of such activated microglia was observed with diffuse plaques. In young APP23 mice , early amyloid deposits were already of dense core nature and were associated with a strong microglial response. Ultrastructurally , bundles of amyloid fibrils , sometimes surrounded by an incomplete membrane , were observed within the microglial cytoplasm. However , microglia with the typical characteristics of phagocytosis were associated more frequently with dystrophic neurites than with amyloid fibrils. Although the present observations cannot unequivocally determine whether microglia are causal , contributory , or consequential to cerebral amyloidosis , our results suggest that microglia are involved in cerebral amyloidosis either by participating in the processing of neuron-derived ␤PP into amyloid fibrils and/or by ingesting amyloid fibrils via an uncommon phagocytotic mechanism. In any case, our observations demonstrate that neuron-derived ␤PP is sufficient to induce not only amyloid plaque formation but also amyloid-associated microglial activation similar to that reported in AD. Moreover, our results are consistent with the idea that microglia activation may be important for the amyloid-associated neuron loss previously reported in these mice. (Am J Pathol 1999, 154:1673-1684)Substantial evidence supports the view that processing of the amyloid-␤ precursor protein (␤PP) and accumulation of the amyloid-␤ peptide (A␤) in the brain of Alzheimer's disease (AD) patients is crucial to the pathophysiology of the disease. 1,2 Senile amyloid plaques in AD brains are surrounded and infiltrated by activated microglia, which acquire an amoeboid morphology and express various proteins involved in the central nervous system inflammation. [3][4][5] The tight association of amyloid fibrils and microglia has suggested that microglia are somehow involved in either the formation or the phagocytosis of amyloid fibrils. 3,6 -10 Activation of microglia is thought to induce an inflammatory response in the central nervous system and to be a mediator of the amyloid-associated neurodegeneration in AD brain. 11,12 The involvement of inflammation in the progress of AD is underlined by clinical studies showing...

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“…Both cassettes were designed to possess the APP signal sequence (17 amino acids), the Ah containing C-terminal 99 amino acids of APP with the V717F mutation (hCTF99(V717F)), and the SV40 polyadenylation sequence (247 bp). Transgene expression was driven by the platelet-derived growth factor (PDGF)-h promoter, which has been used to produce a high level of transgene expression in the brain (Sasahara et al, 1991;Games et al, 1995;Irizarry et al, 1997;Lee et al, 2004). The heterologous intron (918 bp) obtained from the human h-globin gene was inserted between the PDGF-h promoter and hCTF99 in the PDGF-intron-hCTF99-pA cassette (Fig.…”

Section: Generation Of Transgenic Mice Expressing Bctf99 In the Brainmentioning

confidence: 99%

Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein

Lee

Song

et al. 2006

Neurobiology of Disease

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Aβ Deposition Is Associated with Neuropil Changes, but not with Overt Neuronal Loss in the Human Amyloid Precursor Protein V717F (PDAPP) Transgenic Mouse

Cited by 475 publications

References 48 publications

Imaging microglial activation and glucose consumption in a mouse model of Alzheimer's disease

Imaging microglial activation and glucose consumption in a mouse model of Alzheimer's disease

Association of Microglia with Amyloid Plaques in Brains of APP23 Transgenic Mice

Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein

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