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A beta Immunotherapy Protects Morphology and Survival of Adult-Born Neurons in Doubly Transgenic APP/PS1 Mice

Biscaro, Barbara; Lindvall, Olle LU ; Hock, Christoph; Ekdahl Clementson, Christine LU and Nitsch, Roger M. (2009) In Journal of Neuroscience 29(45). p.14108-14119
Abstract
The hippocampus is heavily affected by progressive neurodegeneration and beta-amyloid pathology in Alzheimer's disease (AD). The hippocampus is also one of the few brain regions that generate new neurons throughout adulthood. Because hippocampal neurogenesis is regulated by both endogenous and environmental factors, we determined whether it benefits from therapeutic reduction of beta-amyloid peptide (A beta)-related toxicity induced by passive A beta immunotherapy. A beta immunotherapy of 8-9-month-old mice expressing familial AD-causing mutations in the amyloid precursor protein and presenilin-1 genes with an antibody against A beta decreased compact beta-amyloid plaque burden and promoted survival of newly born neurons in the hippocampal... (More)
The hippocampus is heavily affected by progressive neurodegeneration and beta-amyloid pathology in Alzheimer's disease (AD). The hippocampus is also one of the few brain regions that generate new neurons throughout adulthood. Because hippocampal neurogenesis is regulated by both endogenous and environmental factors, we determined whether it benefits from therapeutic reduction of beta-amyloid peptide (A beta)-related toxicity induced by passive A beta immunotherapy. A beta immunotherapy of 8-9-month-old mice expressing familial AD-causing mutations in the amyloid precursor protein and presenilin-1 genes with an antibody against A beta decreased compact beta-amyloid plaque burden and promoted survival of newly born neurons in the hippocampal dentate gyrus. As these neurons matured, they exhibited longer dendrites with more complex arborization compared with newly born neurons in control-treated transgenic littermates. The newly born neurons showed signs of functional integration indicated by expression of the immediate-early gene Zif268 in response to exposure to a novel object. A beta immunotherapy was associated with higher numbers of synaptophysin-positive synaptic boutons. Labeling dividing progenitor cells with a retroviral vector encoding green fluorescent protein (GFP) showed that A beta immunotherapy restored the impaired dendritic branching, as well as the density of dendritic spines in new mature neurons. The presence of cellular prion protein (PrPc) on the dendrites of the GFP(+) newly born neurons is compatible with a putative role of PrPc in mediating A beta-related toxicity in these cells. In addition, passive A beta immunotherapy was accompanied by increased angiogenesis. Our data establish that passive A beta immunotherapy can restore the morphological maturation of the newly formed neurons in the adult hippocampus and promote angiogenesis. These findings provide evidence for a role of A beta immunotherapy in stimulating neurogenesis and angiogenesis in transgenic mouse models of AD, and they suggest the possibility that A beta immunotherapy can recover neuronal and vascular functions in brains with beta-amyloidosis. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Neuroscience
volume
29
issue
45
pages
14108 - 14119
publisher
Society for Neuroscience
external identifiers
  • wos:000271664000006
  • scopus:70449669057
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.2055-09.2009
language
English
LU publication?
yes
id
4c5aa487-0ddd-43fc-84ff-734a27ca91b0 (old id 1518803)
date added to LUP
2009-12-28 14:03:38
date last changed
2017-09-17 06:51:59
@article{4c5aa487-0ddd-43fc-84ff-734a27ca91b0,
  abstract     = {The hippocampus is heavily affected by progressive neurodegeneration and beta-amyloid pathology in Alzheimer's disease (AD). The hippocampus is also one of the few brain regions that generate new neurons throughout adulthood. Because hippocampal neurogenesis is regulated by both endogenous and environmental factors, we determined whether it benefits from therapeutic reduction of beta-amyloid peptide (A beta)-related toxicity induced by passive A beta immunotherapy. A beta immunotherapy of 8-9-month-old mice expressing familial AD-causing mutations in the amyloid precursor protein and presenilin-1 genes with an antibody against A beta decreased compact beta-amyloid plaque burden and promoted survival of newly born neurons in the hippocampal dentate gyrus. As these neurons matured, they exhibited longer dendrites with more complex arborization compared with newly born neurons in control-treated transgenic littermates. The newly born neurons showed signs of functional integration indicated by expression of the immediate-early gene Zif268 in response to exposure to a novel object. A beta immunotherapy was associated with higher numbers of synaptophysin-positive synaptic boutons. Labeling dividing progenitor cells with a retroviral vector encoding green fluorescent protein (GFP) showed that A beta immunotherapy restored the impaired dendritic branching, as well as the density of dendritic spines in new mature neurons. The presence of cellular prion protein (PrPc) on the dendrites of the GFP(+) newly born neurons is compatible with a putative role of PrPc in mediating A beta-related toxicity in these cells. In addition, passive A beta immunotherapy was accompanied by increased angiogenesis. Our data establish that passive A beta immunotherapy can restore the morphological maturation of the newly formed neurons in the adult hippocampus and promote angiogenesis. These findings provide evidence for a role of A beta immunotherapy in stimulating neurogenesis and angiogenesis in transgenic mouse models of AD, and they suggest the possibility that A beta immunotherapy can recover neuronal and vascular functions in brains with beta-amyloidosis.},
  author       = {Biscaro, Barbara and Lindvall, Olle and Hock, Christoph and Ekdahl Clementson, Christine and Nitsch, Roger M.},
  issn         = {1529-2401},
  language     = {eng},
  number       = {45},
  pages        = {14108--14119},
  publisher    = {Society for Neuroscience},
  series       = {Journal of Neuroscience},
  title        = {A beta Immunotherapy Protects Morphology and Survival of Adult-Born Neurons in Doubly Transgenic APP/PS1 Mice},
  url          = {http://dx.doi.org/10.1523/JNEUROSCI.2055-09.2009},
  volume       = {29},
  year         = {2009},
}