Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice - PubMed (original) (raw)

Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice

S Capsoni et al. Proc Natl Acad Sci U S A. 2000.

Abstract

Neurotrophin nerve growth factor (NGF) has been suggested to be involved in age-related neurodegenerative diseases, but no transgenic model is currently available to study this concept. We have obtained transgenic mice expressing a neutralizing anti-NGF recombinant antibody, in which the levels of antibodies are three orders of magnitude higher in adult than in newborn mice [F.R., S. C. , A.C., E. Di Daniel, J. Franzot, S. Gonfloni, G. Rossi, N. B. & A. C. (2000) J. Neurosci., 20, 2589-2601]. In this paper, we analyze the phenotype of aged anti-NGF transgenic mice and demonstrate that these mice acquire an age-dependent neurodegenerative pathology including amyloid plaques, insoluble and hyperphosphorylated tau, and neurofibrillary tangles in cortical and hippocampal neurons. Aged anti-NGF mice also display extensive neuronal loss throughout the cortex, cholinergic deficit in the basal forebrain, and behavioral deficits. The overall picture is strikingly reminiscent of human Alzheimer's disease. Aged anti-NGF mice represent, to our knowledge, the most comprehensive animal model for this severe neurodegenerative disease. Also, these results demonstrate that, in mice, a deficit in the signaling and/or transport of NGF leads to neurodegeneration.

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Figures

Figure 1

Figure 1

Dilation of lateral ventricles and cholinergic deficit in aged anti-NGF mice. Dilation of brain lateral ventricles in cresyl violet counterstained sections from anti-NGF transgenic mice (a) compared with age-matched controls (b). The communication between the two ventricles is because of mechanical rupture of the dorsal fornix, whose width is consistently reduced in all anti-NGF mice. (c and d) Staining for ChAT in the basal forebrain of anti-NGF transgenic mice (c) and control mice (d). Bar = 400 μm (a and b), 200 μm (c and d).

Figure 2

Figure 2

Amyloid deposits in the cortex of aged anti-NGF transgenic mice. Anti-APP immunoreactivity in cortical sections from anti-NGF (a) and control mice (b). The numerous extracellular amyloid deposits found in the cortex of anti-NGF transgenic mice show, at high magnification (c), a fibrillary nature. Bar = 75 μm (a and b), 25 μm (c).

Figure 3

Figure 3

τ immunoreactivity in the brains of anti-NGF and control mice. (a) mAb Alz50 labels hippocampal interneurones (arrows) and glial cells (asterisk) in anti-NGF mice. (c) mAb AT8 labels cortical neurones in anti-NGF mice. No labeling is observed in control mice (b and d). (e) mAb AT8 labels tangle-like structures in neurones (arrow), neuropil threads (arrowhead), and extracellular neurofibrillary deposits (asterisk) in the cortex of anti-NGF mice. (f) Treatment of cortical slices from anti-NGF mice with AP abolishes the labeling by mAb AT8. (g and h) DNA fragmentation in cortical neurones of anti-NGF (g) and control mice (h). Bar = 25 μm (a, b, e, f), 75 μm (c, d, g, h).

Figure 4

Figure 4

Western analysis of brain extracts from anti-NGF and control mice. Soluble brain extracts: blots were probed with mAbs YOL1 (a), 7.51 (b), PHF-1 (c Upper), PHF-1 after AP treatment (c Lower), AT8 (d), and anti-APP (f). (e) High molecular-weight PHF-1-immunoreactive τ in insoluble extracts from anti-NGF mice. In a and b and d–f, lanes 1–4 refer to controls and lanes 5–7 refer to anti-NGF mice. In c, lanes 1–2 refer to controls and lanes 3–5 to anti-NGF mice. Graphs report quantitative determinations of the intensities of relevant bands. In e, high molecular-weight immunoreactivity was included in the quantification. In f, two groups of bands were considered separately, around 120 kDa and around 25 kDa, respectively. Data represent the average of three experiments for each antibody. Mean ± SEM is shown (P < 0.05).

Figure 5

Figure 5

Immunostaining with the antitangle antibody mAb NFT200. (a–c) Sections through the parietal cortex (a, b) and the entorhinal cortex (c) of anti-NGF transgenic mice. The NFT200 antibody reveals the presence of tangles in pyramidal cells (arrows) and of dystrophic neurites (arrowheads). (d) No labeling is seen in sections from transgenic control mice. Bar = 25 μm.

Figure 6

Figure 6

Behavioral analysis. (A) Spatial learning curves for aged anti-NGF transgenic (n = 6, filled circles) and control mice (n = 6, open circles) mice in an eight-arm radial maze (four arms baited). Vertical bars are the standard errors. The number of arm entries necessary to find all four food pellets is reported as a function of time. Retention test 31 days after the end of the learning test. Transfer test started the day after the retention test. (B) Object recognition test revealing impairment in discrimination tasks. *, P < 0.03.

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