Transthyretin accelerates vascular Abeta deposition in a mouse model of Alzheimer's disease - PubMed (original) (raw)
Transthyretin accelerates vascular Abeta deposition in a mouse model of Alzheimer's disease
Henny Wati et al. Brain Pathol. 2009 Jan.
Abstract
Transthyretin (TTR) binds amyloid-beta (Abeta) and prevents Abeta fibril formation in vitro. It was reported that the lack of neurodegeneration in a transgenic mouse model of Alzheimer's disease (AD) (Tg2576 mouse) was associated with increased TTR level in the hippocampus, and that chronic infusion of anti-TTR antibody into the hippocampus of Tg2576 mice led to increased local Abeta deposits, tau hyperphosphorylation and apoptosis. TTR is, therefore, speculated to prevent Abeta pathology in AD. However, a role for TTR in Abeta deposition is not yet known. To investigate the relationship between TTR and Abeta deposition, we generated a mouse line carrying a null mutation at the endogenous TTR locus and the human mutant amyloid precursor protein cDNA responsible for familial AD (Tg2576/TTR(-/-) mouse) by crossing Tg2576 mice with TTR-deficient mice. We asked whether Abeta deposition was accelerated in Tg2576/TTR(-/-) mice relative to the heterozygous mutant Tg2576 (Tg2576/TTR(+/-)) mice. Contrary to our expectations, the degree of total and vascular Abeta burdens in the aged Tg2576/TTR(-/-) mice was significantly reduced relative to the age-matched Tg2576/TTR(+/-) mice. Our experiments present, for the first time, compelling evidence that TTR does not suppress but rather accelerates vascular Abeta deposition in the mouse model of AD.
Figures
Figure 1
Western blotting analysis of full‐length amyloid precursor protein (APP). The arrow on the left indicates the location of full‐length APP.
Figure 2
The Aβ burden in the brain of Tg2576/TTR +/− and Tg2576/TTR −/− mice. The total Aβ burden (vascular amyloid and plaques) (A) vascular Aβ burden (B) and Aβ plaque burden (C) in the entire cerebral cortex were calculated by dividing total area of Aβ deposits by total area of analyzed cortex. The hippocampal total Aβ burden (D) was calculated by dividing area of total Aβ deposits (vascular amyloid and plaques) by area of analyzed hippocampus. All data are expressed as mean ± standard error of the mean. Numbers in parentheses denote numbers of mice examined. *P < 0.05. TTR = transthyretin.
Figure 3
Immunohistochemistry of Tg2576/TTR +/− and Tg2576/TTR −/− brains. Immuno‐labeling of left hemi‐brain sections of 18‐month‐old Tg2576/TTR +/− and Tg2576/TTR −/− mice with Ab9204. A. The higher magnification of the hippocampal Aβ plaque with giant cores indicated by an arrowhead in A (B, left panels). Serial sections (5 µm) were labeled with AT8, and anti‐phosphorylated tau (Thr231). AT8 and Thr‐231 labeled punctate dystrophic neurites in and around Aβ plaques (B, middle and right panels, respectively). Scale bar; 50 µm. The hippocampal dentate gyrus areas of 18‐month‐old Tg2576/TTR +/− and Tg2576/TTR −/− mice stained with transferase‐mediated dUTP nick end labeling. C. No apoptotic cells were found in the hippocampus. A DNaseI‐treated sample was stained in parallel with the samples as a positive control. Scale bar; 100 µm. TTR = transthyretin.
Figure 4
The Aβ level in the brain of Tg2576/TTR +/− and Tg2576/TTR −/− mice. The Aβ40 (A,B) and Aβ42 (C,D) in Tg2576/TTR +/− and Tg2576/TTR −/− brains were quantified by sandwich enzyme‐linked immunosorbent assay. The samples were sequentially extracted in 2% sodium dodecylsulfate (SDS) (A,C) and 70% FA (B,D). All data are expressed as mean ± standard error of the mean. Numbers in parentheses denote numbers of mice examined. *P < 0.05, **P < 0.01. TTR = transthyretin.
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References
- Alonzo NC, Hyman BT, Rebeck GW, Greenberg SM (1998) Progression of cerebral amyloid angiopathy: accumulation of amyloid‐beta40 in affected vessels. J Neuropathol Exp Neurol 57:353–359. - PubMed
- Biroccio A, Del Boccio P, Panella M, Bernardini S, Di Ilio C, Gambi D et al (2006) Differential post‐translational modifications of transthyretin in Alzheimer's disease: a study of the cerebral spinal fluid. Proteomics 6:2305–2313. - PubMed
- Borchelt DR, Ratovitski T, Van Lare J, Lee MK, Gonzales V, Jenkins NA et al (1997) Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19:939–945. - PubMed
- Botto M, Hawkins PN, Bickerstaff MC, Herbert J, Bygrave AE, McBride A et al (1997) Amyloid deposition is delayed in mice with targeted deletion of the serum amyloid P component gene. Nat Med 3:855–859. - PubMed
- Braak H, Braak E (1991) Neuropathological stageing of Alzheimer‐related changes. Acta Neuropathol (Berl) 82:239–259. - PubMed
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