RESUMO
Alzheimer's disease (AD) is a common form of dementia characterized by amyloid plaque deposition, tau pathology, neuroinflammation, and neurodegeneration. Mouse models recapitulate some key features of AD. For instance, the B6.APP/PS1 model (carrying human transgenes for mutant forms of APP and PSEN1) shows plaque deposition and neuroinflammation involving both astrocytes and microglia beginning around 4-6 months of age. However, significant tau pathology and neurodegeneration are not apparent in this model even when assessed at old age. Therefore, this model is ideal for studying neuroinflammatory responses to amyloid deposition. Here, RNA sequencing of brain and retinal tissue, generalized linear modeling (GLM), functional annotation followed by validation by immunofluorescence was performed in B6.APP/PS1 mice to determine the earliest molecular changes prior to and around the onset of plaque deposition (2-6 months of age). Multiple pathways were shown to be activated in response to amyloid deposition including the JAK/STAT and NALFD pathways. Putative, cell-specific targets of STAT3, a central component of the JAK/STAT pathway, were identified that we propose provide more precise options for assessing the potential for targeting activation of the JAK/STAT pathway as a treatment for human AD. In the retina, GLM predicted activation of vascular-related pathways. However, many of the gene expression changes comparing B6 with B6.APP/PS1 retina samples occurred prior to plaque onset (2 months of age). This suggests retinal changes in B6.APP/PS1 mice may be an artefact of overexpression of mutant forms of APP and PSEN1 providing limited translatability to human AD. Therefore, caution should be taken when using this mouse model to assess the potential of using the eye as a window to the brain for AD.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Encéfalo/metabolismo , Encéfalo/patologia , Presenilina-1/genética , Retina/metabolismo , Retina/patologia , Animais , Sequência de Bases , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Modelos Lineares , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Hepatopatia Gordurosa não Alcoólica/genética , Placa Amiloide/genética , Placa Amiloide/patologia , Fator de Transcrição STAT3/genética , Transdução de Sinais/genéticaRESUMO
Classical laboratory strains show limited genetic diversity and do not harness natural genetic variation. Mouse models relevant to Alzheimer's disease (AD) have largely been developed using these classical laboratory strains, such as C57BL/6J (B6), and this has likely contributed to the failure of translation of findings from mice to the clinic. Therefore, here we test the potential for natural genetic variation to enhance the translatability of AD mouse models. Two widely used AD-relevant transgenes, APPswe and PS1de9 (APP/PS1), were backcrossed from B6 to three wild-derived strains CAST/EiJ, WSB/EiJ, PWK/PhJ, representative of three Mus musculus subspecies. These new AD strains were characterized using metabolic, functional, neuropathological and transcriptional assays. Strain-, sex- and genotype-specific differences were observed in cognitive ability, neurodegeneration, plaque load, cerebrovascular health and cerebral amyloid angiopathy. Analyses of brain transcriptional data showed strain was the greatest driver of variation. We identified significant variation in myeloid cell numbers in wild type mice of different strains as well as significant differences in plaque-associated myeloid responses in APP/PS1 mice between the strains. Collectively, these data support the use of wild-derived strains to better model the complexity of human AD.
Assuntos
Doença de Alzheimer/genética , Modelos Animais de Doenças , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Animais Selvagens/genética , Encéfalo/metabolismo , Variação Genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Placa Amiloide , Presenilina-1/genética , Reprodutibilidade dos TestesRESUMO
Environmental enrichment is an essential component of laboratory animal housing that allows animals to engage in natural behaviors in an otherwise artificial setting. Previous research by the authors suggested that, compared with synthetic enrichment materials, natural materials were associated with lower stress levels in mice. Here, the authors compare the effects of different enrichment materials on stress, memory and exploratory behavior in Swiss Webster mice. Mice that were provided with natural enrichment materials had lower stress levels, better memory and greater exploratory behavior than did mice provided with synthetic enrichment materials or with no enrichment materials. These findings suggest that provision of natural enrichment materials can improve well-being of laboratory mice.
