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Accelerated Amyloid Disposition in the Brains of Transgenic Mice Coexpressing Mutant Presenilin 1 and Amyloid Precursor Proteins
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Alzheimer's presentation
- 1. Date Accelerated Amyloid Deposition in the Brains of Transgenic Mice Coexpressing Mutant Presenilin 1 and Amyloid Precursor Proteins Goldy Landau
- 2. What is Early Onset Familial Alzheimer’s Disease? ✤ Neurodegenerative disease ✤ Age of onset before 50 years old ✤ Cognitive dysfunctions ✤ Memory loss ✤ Dementia ✤ Deterioration of language functions ✤ Hereditary
- 4. Biological Basis of FAD ✤ Amyloid precursor protein (APP) generates ℬ-amyloid fragments, which compose the amyloid plaque deposits. . ✤ Early onset AD are familial (FAD) autosomal dominant disorders caused by mutations in the presenilin 1 (PS1) gene, the presenilin 2 (PS2) gene, or the amyloid precursor protein (APP) gene. ✤ Genes influencing early onset of AD appear to be caused by mutations in at least three different genes such as Amyloid Precursor Protein (APP), Presenilin 1 (PS1) and Presenilin 2 (PS2). ✤ Mutations in these genes accelerate the production of Aβ. Mutations in APP increase the amount, length, or fibrillogenic properties of Aℬ amyloid fragments.
- 5. ✤ In experimental settings, FAD-linked presenilin variants influence processing of the amyloid precursor protein (APP), leading to elevated levels of the highly fibrillogenic Aℬ1–42 peptides that are deposited in the brains of Alzheimer Disease (AD) patients. ✤ This study demonstrates that transgenic animals that coexpress an FAD- linked human PS1 variant (A246E), and a chimeric mouse/human APP harboring mutations linked to Swedish FAD kindreds (APP swe), develop numerous amyloid deposits much earlier than age-matched mice expressing APP swe and wild-type Hu PS1 or APP swe alone. ✤ These results provide evidence for the view that one pathogenic mechanism by which (FAD-linked mutant) PS1 causes AD, is to accelerate the rate of ℬ- amyloid deposition in brain.
- 6. 01 ✤ To test directly whether the expression of FAD mutant PS1 promotes amyloid deposition, we examined the brains of aged (12-month-old) transgenic mice that coexpress Hu PS1-A246E and APP swe. Mice carry a transgene coding for the protein of human Alzheimer β-amyloid (Aβ) precursor protein carrying the Swedish mutation ✤ Expresses high concentrations of the mutant Aβ, develops significant amyloid plaques and displays memory deficits ✤ Premature mortality Alzheimer’s APP SWE Mice
- 7. Results ✤ In examinations of mice expressing these transgenes, we demonstrated that the ratio of Aℬ is elevated by ℬ50% in doubly transgenic mice expressing APP swe and Hu PS1-A246E, as compared with transgenic mice expressing APP swe alone or doubly transgenic mice coexpressing wild-type Hu PS1 and APP swe.
- 8. Results ✤ Transgenic mice that over-expressed mutant presenilin-1 show an increase of beta-amyloid-42(43) in the brain, which suggest presenilin-1 plays an important role in beta-amyloid regulation and can be highly related to Alzheimer’s disease.
- 9. Procedure ✤ To test directly whether the expression of FAD mutant PS1 promotes amyloid deposition, this study examines extent and frequency of Aℬ deposits in 12-month-old mice that: ✤ coexpress Hu PS1-A246E and APP swe, ✤ coexpress wild-type Hu PS1 and APP swe, ✤ express APP swe alone, and ✤ express mutant PS1 alone.
- 10. Results ✤ We demonstrate that only mice coexpressing Hu PS1-A246E and APP swe develop Aℬ deposits by 12 months of age. ✤ Coexpression of Hu PS1-A246E with APP swe reduces the interval of the formation of initial Aℬ deposits from ✤ 18 months for APP swe alone to ✤ 9 months for APP swe with Hu PS1-A246E. ✤ These data provide strong evidence in support of the hypothesis that a principal pathway by which mutations in PS1 predispose individuals to FAD is to accelerate Aℬ deposition.
- 11. 01 Mice Coexpressing Hu PS1-A246E and APP swe Develop A Deposits
Editor's Notes
- A mutation in the gene that makes APP is believed to be responsible for 5 to 20 percent of all early onset familial Alzheimer's disease. Some AD cases occur relatively early and are familial (FAD) autosomal dominant disorders caused by mutations in the presenilin 1 (PS1) gene, the presenilin 2 (PS2) gene, or the amyloid precursor protein (APP) gene. ℬ-amyloid (Aℬ) peptides are generated from the amyloid precursor protein (APP), and FAD-linked mutations in APP increase the amount, length, or fibrillogenic properties of Aℬ species. Recent studies indicate that FAD mutant PS1 alters APP processing to enhance the generation of Aℬ1–42 peptides, which appear to be more fibrillogenic than Aℬ1–40. Patient plasma, as well as conditioned medium of fibroblast cultures from patients with FAD-linked PS1 and PS2 variants and conditioned medium from transfected mammalian cells expressing mutant PS1 and PS2 variants, have been shown to contain higher levels of Aℬ1–42 than relevant controls. In experimental settings, FAD-linked presenilin variants influence processing of the amyloid precursor protein (APP), leading to elevated levels of the highly fibrillogenic Aℬ1–42 peptides that are deposited in the brains of Alzheimer Disease (AD) patients. To examine the impact of mutant PS1 on Aℬ1–42 levels in an in vivo setting, we produced transgenic mice that coexpress FAD mutant human (Hu) PS1-A246E and a chime- ric mouse/human (Mo/Hu) APP695 harboring a Hu Aℬ domain and mutations linked to Swedish FAD pedigrees (APP swe). In comparison to transgenic mice expressing APP swe alone or doubly transgenic mice coexpressing wild-type Hu PS1 and APP swe, mice co- expressing Hu PS1-A246E and APP swe contained higher concentrations of Aℬ1–42 in brain tissue (Borchelt et al., 1996b). Similarly, mutant PS1 selectively influences the processing of endogenous mouse APP and wild-type human APP to increase production of Aℬ1–42 in transgenic mouse brains.
- So the mice already had alzheimers from the APP gene. They wanted to see the role of PS1 for b- amyloid being created in the brain, The activities of presenilin 1 (PS1) and 2 modulate the proteolytic processing of amyloid precursor proteins to produce Aβ1–42, and mutations in these proteins are associated with an accelerated rate of Aβ deposition. PS1 and PS2 themselves are subject to a highly-regulated endoproteolytic cleavage to generate stable 27 kDa N-terminal and 17 kDa C-terminal fragments. Here, we examined the relationship between the regulated cleavage of PS1 and the acceleration of Aβ deposition in transgenic mice that co-express Mo/Hu APPswe and varied levels mutant PS1 (A246E variant). The steady-state levels of the N- and C-terminal fragments of mutant PS1 in mice expressing low levels of mRNA were similar to that of mice expressing high levels of mRNA. Only mice expressing high levels of transgene mRNA accumulated uncleaved full-length protein. In mice co-expressing low levels of PS1A246E mRNA with Mo/Hu APPswe the age of appearance of Aβ deposits was similar to that of mice co-expressing expressing Mo/Hu APPswe with very high levels of mutant PS1. Our findings demonstrate that the levels of accumulated human PS1 N- and C-terminal fragments do not increase in proportion to the level of transgene mRNA and that similarly, the magnitude by which mutant PS1 accelerates the deposition of β-amyloid is not proportional to the level of transgene expression.
- Transgenic mice that express a mutated form of APP, Expressing mutant amyloid precursor protein (APPswe) which increases Abeta42 production and provides a model of Alzheimer-type amyloidosis. Mice carry a transgene coding for the protein of human Alzheimer β-amyloid (Aβ) precursor protein Expresses high concentrations of the mutant Aβ, develops significant amyloid plaques and displays memory deficits Useful for the study of APP expression, amyloid plaque formation, neuronal decline and memory loss associated with Alzheimer's disease (AD) as well as the study of drugs designed for treatment or prevention of Alzheimer's disease Premature mortality is an expected phenotype of this line, with mortality of 20% anticipated, particularly in males.
- We demonstrate that only mice coexpressing Hu PS1-A246E and APP swe develop Aℬ deposits by 12 months of age. Moreover, we demonstrate that coexpression of Hu PS1-A246E with APP swe reduces the interval of the formation of initial Aℬ deposits from 18 months for APP swe alone to 9 months for APP swe with Hu PS1-A246E. These data provide strong evidence in support of the hypothesis that a principal pathway by which mutations in PS1 predispose individuals to FAD is to accelerate Aℬ deposition.
- In experimental settings, FAD-linked presenilin variants influence processing of the amyloid precursor protein (APP), leading to elevated levels of the highly fibrillogenic Aℬ1–42 peptides that are deposited in the brains of Alzheimer Disease (AD) patients. Patients with FAD-linked PS1 and PS2 variants and conditioned medium from transfected mammalian cells expressing mutant PS1 and PS2 variants, have been shown to contain higher levels of Aℬ1–42 than relevant controls. To examine the impact of mutant PS1 on Aℬ1–42 levels in an in vivo setting, we produced transgenic mice that coexpress FAD mutant human (Hu) PS1-A246E and a chimric mouse/human (Mo/Hu) APP695 harboring a Hu Aℬ domain and mutations linked to Swedish FAD pedigrees (APP swe). In comparison to transgenic mice expressing APP swe alone or doubly transgenic mice coexpressing wild-type Hu PS1 and APP swe, mice co- expressing Hu PS1-A246E and APP swe contained higher concentrations of Aℬ1–42 in brain tissue. Similarly, mutant PS1 selectively influences the processing of endogenous mouse APP and wild-type human APP to increase production of Aℬ1–42 in transgenic mouse brains.
- (A–F) 12-month-old transgenic mice that coexpress Hu PS1-A246E and APP swe ([A] and [D]), APP swe alone ([B] and [E]), Hu PS1-A246E alone ([C] and [F]) (A–C) Hippocampus and occipital cortex. (D–F) Frontal cortex. (G–I) Sections of hippocampus from 12-month-old mice coexpressing Hu PS1-A246E and APP swe stained with another stain