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. 2002 Nov 15;22(22):9785-93.
doi: 10.1523/JNEUROSCI.22-22-09785.2002.

Evidence that synaptically released beta-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice

Orly Lazarov  1 , Michael Lee, Daniel A Peterson, Sangram S Sisodia
Affiliations

Evidence that synaptically released beta-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice

Orly Lazarov et al. J Neurosci. .

Abstract

A neuropathological hallmark of Alzheimer's disease is the deposition of amyloid-beta (Abeta) peptides in senile plaques in the hippocampus and cerebral cortex. Abeta is derived from larger integral membrane proteins termed amyloid precursor proteins (APP). We demonstrated previously that APP, synthesized by neurons in the entorhinal cortex, is transported via the perforant pathway to presynaptic terminals in the dentate gyrus. We reported that, although full-length APP and membrane-tethered, C-terminal APP derivatives (APP-CTFs) accumulate at terminal fields, the production of Abeta peptides at these sites was indeterminate. To test the hypothesis that APP-CTFs, generated from axonally transported APP, are further metabolized to Abeta peptides that are subsequently released and deposited proximal to nerve terminals, we created unilateral knife lesions of the perforant pathway of transgenic mice that exhibit hippocampal amyloid deposits. We observed pronounced reductions in amyloid burden in the ipsilateral dentate gyrus, findings that lead us to conclude that axonally transported APP gives rise to Abeta peptides that are released from presynaptic sites in the dentate gyrus and deposited in extracellular plaques. Moreover, our findings are consistent with the view that Abeta deposits are dynamic structures and that the perforant path lesion alters the equilibrium between Abeta production-deposition toward clearance as a consequence of blocked axonal transport of APP from the entorhinal cortex to terminal fields in the hippocampus.

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Figures

Fig. 1.
Fig. 1.
Representative images of amyloid immunoreactivity in the dentate gyrus (left panels; DG) and hippocampus (right panels; HIPP) of unlesioned transgenic mice (A, 6-month-old mouse;B, 8-month-old mouse; C, 13-month-old mouse). Amyloid immunoreactivity in the left side (DG-I,HIPP-I) was compared with that detected in the contralateral (right) side (DG-C,HIPP-C). Amyloid was detected by immunolabeling with 6E10 antibodies. No significant difference in amyloid immunoreactivity could be detected. Scale bars, 250 μm.
Fig. 2.
Fig. 2.
Quantitative analysis of amyloid burden in the hippocampus of unlesioned mice. For each individual animal analyzed, amyloid burden in the left side was compared with the burden in the right side in both the hippocampus (left) and the dentate gyrus (right). The ratio between the hemispheres is indicated. No difference in amyloid burden could be observed.
Fig. 3.
Fig. 3.
Representative images of amyloid immunoreactivity in the dentate gyrus (left panels; DG) and hippocampus (right panel; HIPP) of perforant pathway-lesioned mice (A, 7-month-old mouse;B, C, 10-month-old mice). Amyloid immunoreactivity in the ipsilateral (lesioned) side (DG-I, HIPP-I) was compared with that in the contralateral side (DG-C,HIPP-C) 1 month after perforant pathway lesion. Amyloid was detected by immunolabeling with 6E10 antibodies. Immunoreactivity of amyloid deposits is reduced in the ipsilateral hippocampus and dentate gyrus compared with the contralateral side. Scale bars, 250 μm.
Fig. 4.
Fig. 4.
Quantitative analysis of amyloid burden in the hippocampus of perforant pathway-lesioned mice 1 month after lesion. Analysis revealed a significant reduction in amyloid burden in the ipsilateral hippocampus (left) and dentate gyrus (right) compared with the contralateral side (the ratio between the hemispheres is indicated). The reduction in amyloid burden in the dentate gyrus was most pronounced.
Fig. 5.
Fig. 5.
Amyloid burden in the ipsilateral and contralateral hippocampus and dentate gyrus of stab wound-treated mice 1 month after treatment. Top panels show 6E10-labeled hippocampus of a stab wound-treated mouse. Bottom panelsshows quantitative analysis of amyloid burden in the ipsilateral (HIPP-I) and contralateral (HIPP-C) hippocampus and dentate gyrus of stab wound-treated mice 1 month after treatment. No significant difference in amyloid burden was found between the ipsilateral and the contralateral hippocampus or dentate gyrus in these animals. Scale bar, 250 μm.
Fig. 6.
Fig. 6.
A, B, Reactive gliosis in the hippocampus and dentate gyrus of unlesioned mice as could be detected by immunostaining using S100β antibodies in dentate gyrus in the left hemisphere (A) and in the right one (B). S100β immunoreactivity (inred) was most pronounced around amyloid deposits (immunostained using 6E10 antibodies; in green). Some overlap between S100β-labeled glia (D) and amyloid deposits (6E10 antibodies; C) could be detected (E, see arrows). F,G, Reactive morphology of glia is reduced in the ipsilateral hippocampus (F) but not in the contralateral one (G) 1 month after perforant pathway lesion. Scale bar, 150 μm.
Fig. 7.
Fig. 7.
Neurofilament morphology in the dentate gyrus–hippocampus as detected by immunolabeling 1 month after perforant pathway lesion. A, B, Contralateral hippocampus (B, high power).C, Ipsilateral hippocampus. Brain sections are double immunolabeled for neurofilament (in green) and β-amyloid (6E10 antibodies; in red). Neuritic atrophy could be detected in the contralateral side. In contrast, neurofilament morphology in the ipsilateral side seems to be recovered, at least in part. Scale bars, 250 μm.
Fig. 8.
Fig. 8.
Quantitative analysis of amyloid burden in the hippocampus of mice after reinnervation of the outer molecular layer of the dentate gyrus. Mice were subject to perforant pathway lesion at 4 months of age. Four months later, brain sections were analyzed for amyloid burden. The ratio between the hemispheres is indicated. No difference in amyloid burden could be observed between the lesioned hippocampus and the unlesioned one.
Fig. 9.
Fig. 9.
Reactive synaptogenesis in the outer molecular layer of mice 4 months after perforant pathway lesion. Brain sections were examined for the presence of the presynaptic marker Bassoon 1 week (A), 1 month (B), or 4 months (C, D) after lesion. Immunoreactivity for Bassoon was easily detected in the ipsilateral hippocampus of 4 month postlesion mice, less pronounced in brain sections of 1 month mice, and barely detected in sections of 1 week postlesioned mice. D, Bassoon and synapsin double-labeled synapses in the dentate gyrus of 4 month postlesion mice. E–G, Synapses could be detected, surrounding amyloid deposits. This close proximity may suggest that the source of deposited material is synapse released. E, Bassoon immunoreactivity in the dentate gyrus of 4 month postlesion mice.F, Amyloid immunoreactivity at the same area asE, as detected by FCA3542 antibodies. G, Merged image of Bassoon and amyloid immunoreactivities.Arrows in G indicate overlapping staining of immunoreactivity for Aβ42 and Bassoon. Scale bars, 250 μm.
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