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- Biscaro, Barbara, et al.
(författare)
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A beta Immunotherapy Protects Morphology and Survival of Adult-Born Neurons in Doubly Transgenic APP/PS1 Mice
- 2009
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Ingår i: The Journal of Neuroscience. - 1529-2401. ; 29:45, s. 14108-14119
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Tidskriftsartikel (refereegranskat)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.
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2. |
- Biscaro, Barbara, et al.
(författare)
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Inhibition of Microglial Activation Protects Hippocampal Neurogenesis and Improves Cognitive Deficits in a Transgenic Mouse Model for Alzheimer's Disease
- 2012
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Ingår i: Neurodegenerative Diseases. - : S. Karger AG. - 1660-2862 .- 1660-2854. ; 9:4, s. 187-198
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Tidskriftsartikel (refereegranskat)abstract
- Background: Activated microglia with macrophage-like functions invade and surround beta-amyloid (A beta) plaques in Alzheimer's disease (AD), possibly contributing to the turnover of A beta, but they can also secrete proinflammatory factors that may be involved in the pathogenesis of AD. Microglia are known to modulate adult hippocampal neurogenesis. Objectives/Methods: To determine the role of microglia on neurogenesis in brains with A beta pathology, we inhibited microglial activation with the tetracycline derivative minocycline in doubly transgenic mice expressing mutant human amyloid precursor protein (APP) and mutant human presenilin-1 (PS1). Results: Minocycline increased the survival of new dentate granule cells in APP/PS1 mice indicated by more BrdU+/NeuN+ cells as compared to vehicle-treated transgenic littermates, accompanied by improved behavioral performance in a hippocampus-dependent learning task. Both brain levels of A beta and A beta-related morphological deficits in the new neurons labeled with GFP-expressing retrovirus were unaffected in minocycline-treated mice. Conclusions: These results suggest a role for microglia in A beta-related functional deficits and in suppressing the survival of new neurons, and show that modulation of microglial function with minocycline can protect hippocampal neurogenesis in the presence of A beta pathology. Copyright (C) 2012 S. Karger AG, Basel
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