RESUMO
Individuals who have Down syndrome (trisomy 21) are at greatly increased risk of developing Alzheimer's disease, characterised by the accumulation in the brain of amyloid-ß plaques. Amyloid-ß is a product of the processing of the amyloid precursor protein, encoded by the APP gene on chromosome 21. In Down syndrome the first site of amyloid-ß accumulation is within endosomes, and changes to endosome biology occur early in Alzheimer's disease. Here, we determine if primary mouse embryonic fibroblasts isolated from a mouse model of Down syndrome can be used to study endosome and APP cell biology. We report that in this cellular model, endosome number, size and APP processing are not altered, likely because APP is not dosage sensitive in the model, despite three copies of App.
Assuntos
Doença de Alzheimer , Síndrome de Down , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Biologia , Síndrome de Down/genética , Síndrome de Down/metabolismo , Endossomos/metabolismo , Fibroblastos/metabolismo , Camundongos , Placa Amiloide/metabolismoRESUMO
People who have Down syndrome are at significantly elevated risk of developing early onset Alzheimer's disease that causes dementia (AD-DS). Here we review recent progress in modeling the development of AD-DS in mouse models. These studies provide insight into mechanisms underlying Alzheimer's disease and generate new clinical research questions. In addition, they suggest potential new targets for disease prevention therapies.
Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Síndrome de Down , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Síndrome de Down/tratamento farmacológico , Síndrome de Down/genética , Síndrome de Down/metabolismo , Síndrome de Down/patologia , CamundongosRESUMO
Apolipoprotein E (APOE) effects on brain function remain controversial. Removal of APOE not only impairs cognitive functions but also reduces neuritic amyloid plaques in mouse models of Alzheimer's disease (AD). Can APOE simultaneously protect and impair neural circuits? Here, we dissociated the role of APOE in AD versus aging to determine its effects on neuronal function and synaptic integrity. Using two-photon calcium imaging in awake mice to record visually evoked responses, we found that genetic removal of APOE improved neuronal responses in adult APP/PSEN1 mice (8-10 mo). These animals also exhibited fewer neuritic plaques with less surrounding synapse loss, fewer neuritic dystrophies, and reactive glia. Surprisingly, the lack of APOE in aged mice (18-20 mo), even in the absence of amyloid, disrupted visually evoked responses. These results suggest a dissociation in APOE's role in AD versus aging: APOE may be neurotoxic during early stages of amyloid deposition, although being neuroprotective in latter stages of aging.
