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. 1997 Dec 15;17(24):9407-14.
doi: 10.1523/JNEUROSCI.17-24-09407.1997.

The beta-amyloid precursor protein of Alzheimer's disease enhances neuron viability and modulates neuronal polarity

R G Perez  1 , H Zheng, L H Van der Ploeg, E H Koo
Affiliations

The beta-amyloid precursor protein of Alzheimer's disease enhances neuron viability and modulates neuronal polarity

R G Perez et al. J Neurosci. .

Abstract

beta-Amyloid precursor protein (betaPP) can reside at neuron and glial cell surfaces or undergo proteolytic processing into secreted fragments. Although betaPP has been studied extensively, its precise physiological role is unknown. A line of transgenic knock-out mice selectively deficient in betaPP survive and breed but exhibit motor dysfunction and brain gliosis, consistent with a physiological role for betaPP in neuron development. To elucidate these functions, we cultured hippocampal neurons from wild-type and betaPP-deficient mice and compared their ability to attach, survive, and develop neurites. We found that hippocampal neurons from betaPP-deficient mice had diminished viability and retarded neurite development. We also compared the effects of betaPP secretory products, released from wild-type astrocytes, on process outgrowth from wild-type and betaPP-deficient hippocampal neurons. Outgrowth was enhanced at 1 d in the presence of wild-type astrocytes, as compared with betaPP-deficient astrocytes. However, by 3 d, neurons had shorter axons but more minor processes with more branching when cocultured with wild-type astrocytes, as compared with betaPP-deficient astrocytes. Our data demonstrate that cell-associated neuronal betaPP contributes to neuron viability, axonogenesis, and arborization and that betaPP secretory products modulate axon growth, dendrite branching, and dendrite numbers.

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Figures

Fig. 1.
Fig. 1.
Live cells and dead cells in neuron/astrocyte cocultures at 3 d in vitro. Intact wild-type (A) and βPP-deficient (B) hippocampal neurons (shown here cocultured with wild-type astrocytes) are among dead cells (at arrowheads in A, B). Live neurons appear brightly stained with calcein-AM and have well developed neurites. Dead cells, labeled by ethidium dimer, are rounded and appear faintly stained (at arrowheads inA, B). C, βPP-deficient hippocampal cultures had significantly fewer live neurons per field whether cocultured with wild-type astrocytes or βPP-deficient astrocytes than did wild-type hippocampal neurons cocultured with either wild-type or βPP-deficient astrocytes in 50 random fields. WT, Wild-type;KO, βPP-deficient knock-out. WT/WT, Wild-type neurons cocultured with wild-type astrocytes;KO/WT, βPP-deficient neurons cocultured with wild-type astrocytes; WT/KO, wild-type neurons cocultured with βPP-deficient knock-out astrocytes; KO/KO, βPP-deficient neurons cocultured with βPP-deficient astrocytes. ANOVA, p < 0.0001. *Significantly different from WT/WT cocultures. Scale bar, 60 μm.
Fig. 2.
Fig. 2.
Stage 3 hippocampal neurons in astrocyte cocultures for 1 d. Proximal and distal portions of each axon (ax) are marked by small arrows for a wild-type neuron cocultured with wild-type astrocytes (A), a βPP-deficient neuron cocultured with wild-type astrocytes (B), a wild-type neuron cocultured with βPP-deficient astrocytes (C), and a βPP-deficient neuron cocultured with βPP-deficient astrocytes (D). The short neurites emanating from the cell body are predendritic, minor processes. WT/WT, Wild-type neurons cocultured with wild-type astrocytes; KO/WT, βPP-deficient neurons cocultured with wild-type astrocytes;WT/KO, wild-type neurons cocultured with βPP-deficient knock-out astrocytes; KO/KO, βPP-deficient neurons cocultured with βPP-deficient astrocytes. Scale bar, 25 μm.
Fig. 3.
Fig. 3.
βPP-related effects on neuron morphology for hippocampal neurons cocultured with wild-type and βPP-deficient astrocytes for 1 d. A, Axon, minor process, and total outgrowth were greatest for wild-type neurons cocultured with wild-type astrocytes (WT/WT). Significantly less axon growth was apparent for βPP-deficient knock-out neurons in both astrocyte conditions and for wild-type neurons cocultured with βPP-deficient astrocytes. B, Branching of axons and minor processes was more pronounced for neurons in WT/WT cultures.C, βPP-deficient neurons, which lack cell-surface βPP, had significantly more minor processes when cocultured with βPP-deficient astrocytes, which do not secrete βPPs or Aβ. WT/WT, Wild-type neurons cocultured with wild-type astrocytes; KO/WT, βPP-deficient knock-out neurons with wild-type astrocytes; WT/KO, wild-type neurons with βPP-deficient knock-out astrocytes; KO/KO, βPP-deficient knock-out neurons with βPP-deficient knock-out astrocytes; O.G., outgrowth; Br., branches. Data are averages of 40 neurons ± SEM. *Significantly different from WT/WT cocultures. Histogram legend in Capplies to A–C.
Fig. 4.
Fig. 4.
Hippocampal neurons cocultured with wild-type and βPP-deficient astrocytes for 3 d. Neurons had extensive axon (ax) and minor process development (small processes emanating from the cell body) by 3 d in vitro. Proximal and distal portions of each axon are indicated by small arrows for a wild-type neuron cocultured with wild-type astrocytes (A), a βPP-deficient neuron cocultured with wild-type astrocytes (B), a wild-type neuron cocultured with βPP-deficient astrocytes (C), and a βPP-deficient neuron cocultured with βPP-deficient astrocytes (D). The developing predendritic, minor processes are more pronounced for neurons cultured with wild-type astrocytes for 3 d (A,B) than for neurons grown with βPP-deficient glia (C, D). WT/WT, Wild-type neurons cocultured with wild-type astrocytes; KO/WT, βPP-deficient neurons cocultured with wild-type astrocytes;WT/KO, wild-type neurons cocultured with βPP-deficient knock-out astrocytes; KO/KO, βPP-deficient neurons cocultured with βPP-deficient astrocytes. Scale bar, 25 μm.
Fig. 5.
Fig. 5.
βPP-related effects on hippocampal neurons grown in coculture with wild-type and βPP-deficient astrocytes for 3 d. A, Axon outgrowth was significantly less for neurons cocultured with wild-type astrocytes, which secrete βPPsand Aβ. Minor process outgrowth was not significantly different for the four coculture conditions. Total outgrowth, which paralleled axon outgrowth, was greater in the absence of βPP secretory products.B, Wild-type neurons, which express cell-surface βPP, had more axon branching than βPP-deficient neurons in both coculture conditions. Minor process branching was enhanced for neurons grown with wild-type astrocytes, which secrete βPPs and Aβ. Total branching was enhanced for wild-type neurons cocultured with wild-type astrocytes (WT/WT). C, More minor processes were produced by neurons cocultured with wild-type astrocytes, which secrete βPPs and Aβ.WT/WT, Wild-type neurons cocultured with wild-type astrocytes; KO/WT, βPP-deficient knock-out neurons with wild-type astrocytes; WT/KO, wild-type neurons with βPP-deficient knock-out astrocytes; KO/KO, βPP-deficient knock-out neurons with βPP-deficient knock-out astrocytes; O.G., outgrowth; Br., branches. Data are averages of 40 neurons ± SEM. *Significantly different from WT/WT cocultures. Histogram legend in Capplies to A–C.
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