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A novel mouse model of Alzheimer's disease with chronic estrogen deficiency leads to glial cell activation and hypertrophy.

ABSTRACT: The role of estrogens in Alzheimer's disease (AD) involving ?-amyloid (A?) generation and plaque formation was mostly tested in ovariectomized mice with or without APP mutations. The aim of the present study was to explore the abnormalities of neural cells in a novel mouse model of AD with chronic estrogen deficiency. These chimeric mice exhibit a total FSH-R knockout (FORKO) and carry two transgenes, one expressing the ?-amyloid precursor protein (APPsw, Swedish mutation) and the other expressing presenilin-1 lacking exon 9 (PS1?9). The most prominent changes in the cerebral cortex and hippocampus of these hypoestrogenic mice were marked hypertrophy of both cortical neurons and astrocytes and an increased number of activated microglia. There were no significant differences in the number of A? plaques although they appeared less compacted and larger than those in APPsw/PS1?9 control mice. Similar glia abnormalities were obtained in wild-type primary cortical neural cultures treated with letrozole, an aromatase inhibitor. The concordance of results from APPsw/PS1?9 mice with or without FSH-R deletion and those with letrozole treatment in vitro (with and without A? treatment) of primary cortical/hippocampal cultures suggests the usefulness of these models to explore molecular mechanisms involved in microglia and astrocyte activation in hypoestrogenic states in the central nervous system.

SUBMITTER: Prat A

PROVIDER: S-EPMC3182380 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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A novel mouse model of Alzheimer's disease with chronic estrogen deficiency leads to glial cell activation and hypertrophy.

Prat Annik A Behrendt Maik M Marcinkiewicz Edwige E Boridy Sebastien S Sairam Ram M RM Seidah Nabil G NG Maysinger Dusica D

Journal of aging research 20110928

The role of estrogens in Alzheimer's disease (AD) involving β-amyloid (Aβ) generation and plaque formation was mostly tested in ovariectomized mice with or without APP mutations. The aim of the present study was to explore the abnormalities of neural cells in a novel mouse model of AD with chronic estrogen deficiency. These chimeric mice exhibit a total FSH-R knockout (FORKO) and carry two transgenes, one expressing the β-amyloid precursor protein (APPsw, Swedish mutation) and the other expressi ...[more]

PMID: 21969914

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Project description:Allergic and atopic disorders have increased over the past few decades and have been associated with neuropsychiatric conditions, such as autism spectrum disorder and asthmatic amyotrophy. Myelitis presenting with neuropathic pain can occur in patients with atopic disorder; however, the relationship between allergic inflammation and neuropathic pain, and the underlying mechanism, remains to be established. We studied whether allergic inflammation affects the spinal nociceptive system. We found that mice with asthma, atopic dermatitis, or atopic diathesis had widespread and significantly more activated microglia and astroglia in the spinal cord than those without atopy, and displayed tactile allodynia. Microarray analysis of isolated microglia revealed a dysregulated phenotype showing upregulation of M1 macrophage markers and downregulation of M2 markers in atopic mice. Among the cell surface protein genes, endothelin receptor type B (EDNRB) was most upregulated. Immunohistochemical analysis revealed that EDNRB expression was enhanced in microglia and astroglia, whereas endothelin-1, an EDNRB ligand, was increased in serum, lungs, and epidermis of atopic mice. No EDNRA expression was found in the spinal cord. Expression of FBJ murine osteosarcoma viral oncogene homolog B was significantly higher in the dorsal horn neurons of asthma mice than nonatopic mice. The EDNRB antagonist BQ788 abolished glial and neural activation and allodynia. We found increased serum endothelin-1 in atopic patients with myelitis and neuropathic pain, and activation of spinal microglia and astroglia with EDNRB upregulation in an autopsied case. These results suggest that allergic inflammation induces diffuse glial activation, influencing the nociceptive system via the EDNRB pathway.Significance statementThe prevalence of allergic disorders has markedly increased over the past few decades. Allergic disorders are associated with neuropsychiatric conditions; however, the relationship between allergic inflammation and CNS complications is unknown. A peculiar myelitis presenting with persistent neuropathic pain has been reported in patients with allergic disorders. We studied how atopy exerts substantial influence on the nociceptive system. We found that mice with allergic disorders had severe allodynia with activated astroglia and microglia, and showed marked upregulation of endothelin-1 (ET-1) receptor type B (EDNRB) in the spinal cord. A selective EDNRB antagonist prevented allodynia and glial activation. Our findings suggest a novel mechanism whereby atopy induces glial activation and neuropathic pain via an ET-1/EDNRB pathway.

Dataset Information

A novel mouse model of Alzheimer's disease with chronic estrogen deficiency leads to glial cell activation and hypertrophy.

Publications

A novel mouse model of Alzheimer's disease with chronic estrogen deficiency leads to glial cell activation and hypertrophy.

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