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Murine Aβ over-production produces diffuse and compact Alzheimer-type amyloid deposits.

Xu G, Ran Y, Fromholt SE, Fu C, Yachnis AT, Golde TE, Borchelt DR - Acta Neuropathol Commun (2015)

Bottom Line: Transgenic overexpression of amyloid precursor protein (APP) genes that are either entirely human in sequence or have humanized Aβ sequences can produce Alzheimer-type amyloidosis in mice, provided the transgenes also encode mutations linked to familial Alzheimer's Disease (FAD).Both lines of mice that produce mouse Aβ develop amyloid deposits, with the moAPPswe/PS1dE9 micedeveloping extracellular compact, cored, neuritic deposits that primarily localize to white matter tracts andmeningial layers, whereas the tet.moAPPsi mice developed extracellular diffuse cortical/hippocampal deposits distributed throughout the parenchyma.These findings demonstrate that murine Aβ peptides have the capacity to produce amyloid deposits that are morphologically similar to deposits found in human AD provided the murine APP gene harbors mutations linked to human FAD.

View Article: PubMed Central - PubMed

Affiliation: Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, 32610, USA.

ABSTRACT

Introduction: Transgenic overexpression of amyloid precursor protein (APP) genes that are either entirely human in sequence or have humanized Aβ sequences can produce Alzheimer-type amyloidosis in mice, provided the transgenes also encode mutations linked to familial Alzheimer's Disease (FAD). Although transgenic mice have been produced that overexpress wild-type mouse APP, no mice have been generated that express mouse APP with FAD mutations. Here we describe two different versions of such mice that produce amyloid deposits consisting of entirely of mouse Aβ peptides. One line of mice co-expresses mouse APP-Swedish (moAPPswe) with a human presenilin exon-9 deleted variant (PS1dE9) and another line expresses mouse APP-Swedish/Indiana (APPsi) using tetracycline-regulated vectors (tet.moAPPsi).

Results: Both lines of mice that produce mouse Aβ develop amyloid deposits, with the moAPPswe/PS1dE9 micedeveloping extracellular compact, cored, neuritic deposits that primarily localize to white matter tracts andmeningial layers, whereas the tet.moAPPsi mice developed extracellular diffuse cortical/hippocampal deposits distributed throughout the parenchyma.

Conclusions: These findings demonstrate that murine Aβ peptides have the capacity to produce amyloid deposits that are morphologically similar to deposits found in human AD provided the murine APP gene harbors mutations linked to human FAD.

No MeSH data available.


Related in: MedlinePlus

Comparison of human and mouse Aβ sequences. The two primary sites of BACE1 cleavages, designated +1 and +11, are noted by arrowheads above the sequences. The 3 sequence differences between human and mouse Aβ at residues 5, 10 and 13 are underlined in bold
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Fig1: Comparison of human and mouse Aβ sequences. The two primary sites of BACE1 cleavages, designated +1 and +11, are noted by arrowheads above the sequences. The 3 sequence differences between human and mouse Aβ at residues 5, 10 and 13 are underlined in bold

Mentions: Mutations in the amino acid sequence of the amyloid precursor protein (APP) influence its cleavage by three types of endo-proteases termed α, β, and γ-secretase [8, 16]. Studies of APP processing by the enzyme BACE1 have demonstrated that this enzyme, which is responsible for the cleavage event at the amino terminus of Aβ, can cleave APP to produce two possible major amino terminal sites, termed +1 and +11 (Fig. 1). For wild-type APP sequence, BACE 1 generally cleaves APP at the +11 site, and after cleavage by γ-secretase, Aβ peptides 11–40 and 11–42 are produced [6]. A third enzyme, termed α-secretase, cleaves APP within the Aβ peptide sequence to produce peptides such as Aβ17-40 and 17–42 (for review see [8, 16]). Importantly, Aβ11-40/42 and 17–40/42 peptides are generally not found as significant components of amyloid plaque lesions that characterize human AD [13, 28]. The major Aβ peptide found in mature neuritic plaques of human AD is Aβ1-42 [19, 30]. Mutations in APP that cause early-onset AD can influence cleavage of APP by either BACE1, γ-secretase, or α-secretase so that a greater percentage of Aβ1-42 peptides are generated by these processes [for review see [8, 16]. Thus, the early-onset of AD in patients harboring mutations in APP is thought to be due to the accelerated deposition of amyloid, which initiates a cascade of pathogenic events to produce full spectrum of AD symptoms [17].Fig. 1


Murine Aβ over-production produces diffuse and compact Alzheimer-type amyloid deposits.

Xu G, Ran Y, Fromholt SE, Fu C, Yachnis AT, Golde TE, Borchelt DR - Acta Neuropathol Commun (2015)

Comparison of human and mouse Aβ sequences. The two primary sites of BACE1 cleavages, designated +1 and +11, are noted by arrowheads above the sequences. The 3 sequence differences between human and mouse Aβ at residues 5, 10 and 13 are underlined in bold
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4644287&req=5

Fig1: Comparison of human and mouse Aβ sequences. The two primary sites of BACE1 cleavages, designated +1 and +11, are noted by arrowheads above the sequences. The 3 sequence differences between human and mouse Aβ at residues 5, 10 and 13 are underlined in bold
Mentions: Mutations in the amino acid sequence of the amyloid precursor protein (APP) influence its cleavage by three types of endo-proteases termed α, β, and γ-secretase [8, 16]. Studies of APP processing by the enzyme BACE1 have demonstrated that this enzyme, which is responsible for the cleavage event at the amino terminus of Aβ, can cleave APP to produce two possible major amino terminal sites, termed +1 and +11 (Fig. 1). For wild-type APP sequence, BACE 1 generally cleaves APP at the +11 site, and after cleavage by γ-secretase, Aβ peptides 11–40 and 11–42 are produced [6]. A third enzyme, termed α-secretase, cleaves APP within the Aβ peptide sequence to produce peptides such as Aβ17-40 and 17–42 (for review see [8, 16]). Importantly, Aβ11-40/42 and 17–40/42 peptides are generally not found as significant components of amyloid plaque lesions that characterize human AD [13, 28]. The major Aβ peptide found in mature neuritic plaques of human AD is Aβ1-42 [19, 30]. Mutations in APP that cause early-onset AD can influence cleavage of APP by either BACE1, γ-secretase, or α-secretase so that a greater percentage of Aβ1-42 peptides are generated by these processes [for review see [8, 16]. Thus, the early-onset of AD in patients harboring mutations in APP is thought to be due to the accelerated deposition of amyloid, which initiates a cascade of pathogenic events to produce full spectrum of AD symptoms [17].Fig. 1

Bottom Line: Transgenic overexpression of amyloid precursor protein (APP) genes that are either entirely human in sequence or have humanized Aβ sequences can produce Alzheimer-type amyloidosis in mice, provided the transgenes also encode mutations linked to familial Alzheimer's Disease (FAD).Both lines of mice that produce mouse Aβ develop amyloid deposits, with the moAPPswe/PS1dE9 micedeveloping extracellular compact, cored, neuritic deposits that primarily localize to white matter tracts andmeningial layers, whereas the tet.moAPPsi mice developed extracellular diffuse cortical/hippocampal deposits distributed throughout the parenchyma.These findings demonstrate that murine Aβ peptides have the capacity to produce amyloid deposits that are morphologically similar to deposits found in human AD provided the murine APP gene harbors mutations linked to human FAD.

View Article: PubMed Central - PubMed

Affiliation: Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, 32610, USA.

ABSTRACT

Introduction: Transgenic overexpression of amyloid precursor protein (APP) genes that are either entirely human in sequence or have humanized Aβ sequences can produce Alzheimer-type amyloidosis in mice, provided the transgenes also encode mutations linked to familial Alzheimer's Disease (FAD). Although transgenic mice have been produced that overexpress wild-type mouse APP, no mice have been generated that express mouse APP with FAD mutations. Here we describe two different versions of such mice that produce amyloid deposits consisting of entirely of mouse Aβ peptides. One line of mice co-expresses mouse APP-Swedish (moAPPswe) with a human presenilin exon-9 deleted variant (PS1dE9) and another line expresses mouse APP-Swedish/Indiana (APPsi) using tetracycline-regulated vectors (tet.moAPPsi).

Results: Both lines of mice that produce mouse Aβ develop amyloid deposits, with the moAPPswe/PS1dE9 micedeveloping extracellular compact, cored, neuritic deposits that primarily localize to white matter tracts andmeningial layers, whereas the tet.moAPPsi mice developed extracellular diffuse cortical/hippocampal deposits distributed throughout the parenchyma.

Conclusions: These findings demonstrate that murine Aβ peptides have the capacity to produce amyloid deposits that are morphologically similar to deposits found in human AD provided the murine APP gene harbors mutations linked to human FAD.

No MeSH data available.


Related in: MedlinePlus