doi: 10.1126/science.1194516. Epub 2010 Oct 21.
Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis
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- PMID:20966215
- PMCID: PMC3233904
- DOI: 10.1126/science.1194516
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Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis
Yvonne S Eisele et al. Science..
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Abstract
The intracerebral injection of β-amyloid-containing brain extracts can induce cerebral β-amyloidosis and associated pathologies in susceptible hosts. We found that intraperitoneal inoculation with β-amyloid-rich extracts induced β-amyloidosis in the brains of β-amyloid precursor protein transgenic mice after prolonged incubation times.
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(A, B) Aβ-immunostained frontal cortex of APP23 mice inoculated intraperitoneally with Tg extract (A) or Wt extract- (B). (C, D) Most induced β-amyloid was vascular (Aβ-CAA), with Aβ-immunoreactivity extending into the brain parenchyma (arrows). Amyloid-laden vessels were congophilic [red in (D); birefringent under cross-polarized light in insert] and often were surrounded by diffuse, Congo red-negative Aβ deposits (arrowheads). (E, F) Analysis of the entire neocortex for Aβ-CAA frequency [indicated are all three (I-III) CAA severity grades (5)], and for total Aβ load in Tg extract-inoculated mice compared with control (Ctr) mice. Cohort 1 consisted of six Tg extract-inoculated mice versus seven untreated control mice. Aβ-CAA: t(11)=6.78 (all severity grades combined), ***p<0.0001; Aβ load: t(11)=8.79, ***p<0.0001.Cohort 2 consisted of five Tg extract-inoculated mice versus five Wt extract-inoculated mice and four PBS-injected mice. These latter two (control) groups did not differ significantly and were combined for analysis. Aβ-CAA: t(12)=7.79, ***p<0.0001; Aβ load t(12)=2.71, *p<0.05. The occasional parenchymal Aβ-deposits in control mice are normal for 9-month-old APP23 mice. Error bars, means ±SEM. Scale bars: [(A) and (B)] 200μm; [0(C) and (D)] 50μm.
(A) Ultrastructural analysis showed amyloid deposition within the vascular basal lamina (BL), with typical amyloid fibrils (arrowheads) extending into the brain parenchyma. Insets are low- and high-magnification views of the examined vessel (L, lumen) and the typical nonbranching amyloid fibrils. (B toE) Vascular amyloid [stained by Congo Red in (B) and (C)] and parenchymal plaques were surrounded by hypertrophic, Iba1-positive microglia (B), Glial fibrillary acidic protein (GFAP)-positive astrocytes (C), hyperphosphorylated tau-positive neurites [(D); asterisk indicates amyloid core], but a paucity of proximate neurons [cresyl-violet stain (E)]. (F andG) Vessels with CAA types II and III showed smooth muscle cell loss at the site of amyloid deposition (arrowheads; confocal image, maximum projection of 5μm z-stack: red, Aβ; green, smooth muscle actin). A normal vessel (G) has a complete ring of smooth muscle cells. (H) Immunoblotting of micropunches of Aβ-immunoreactive material revealed the expected Aβ band. Synthetic Aβ40/42 is shown as control. Markers, 3 and 6 kD. Scale bars: (A) 1μm (insets, 5 and 0.5 μm); [(B) to (E)] 50μm; [(F) and (G)] 10μm.
Comment in
- Medicine. Prion-like behavior of amyloid-beta.Kim J, Holtzman DM.Kim J, et al.Science. 2010 Nov 12;330(6006):918-9. doi: 10.1126/science.1198314.Science. 2010.PMID:21071652No abstract available.
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- Prusiner SB. Prion Biology and Diseases. 2. Cold Spring Harbor Laboratory Press; Cold Spring Harbor, NY: 2004.
- Kimberlin RH, Walker CA. J Comp Path. 1978;88:39. - PubMed
Materials and methods are available as supporting material onScience Online.
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