Background: Activated microglia with macrophage-like functions invade and surround β-amyloid (Aβ) plaques in Alzheimer’s disease (AD), possibly contributing to the turnover of Aβ, 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 Aβ 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 Aβ and Aβ-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 Aβ-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 Aβ pathology.
The hippocampus is heavily affected by progressive neurodegeneration and -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 -amyloid peptide (A)-related toxicity induced by passive A immunotherapy. A 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 decreased compact -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 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 immunotherapy restored the impaired dendritic branching, as well as the density of dendritic spines in new mature neurons. The presence of cellular prion protein (PrP c ) on the dendrites of the GFP ϩ newly born neurons is compatible with a putative role of PrP c in mediating A-related toxicity in these cells. In addition, passive A immunotherapy was accompanied by increased angiogenesis. Our data establish that passive A 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 immunotherapy in stimulating neurogenesis and angiogenesis in transgenic mouse models of AD, and they suggest the possibility that A immunotherapy can recover neuronal and vascular functions in brains with -amyloidosis.
Purpose: Tc-99m methylene diphosphonate ([ 99m Tc]MDP) is an in vivo bone imaging agent that also accumulates in injured skeletal muscle cells. The objective of this study was to investigate if [ 99m Tc]MDP could be used to detect muscle injury in the mdx mouse model of Duchenne muscular dystrophy (DMD). Procedures: Static whole-body single-photon emission computed tomography/computed tomography (CT) scans were acquired at 2 h post-injection of [ 99m Tc]MDP in two cohorts of animals at different sites: one cohort of mice at 6, 15, and 19 weeks of age, and a separate cohort at 16 weeks. The second cohort was also imaged with high-resolution CT at 8 weeks. Results: mdx mice had higher [ 99m Tc]MDP uptake and significantly higher [ 99m Tc]MDP concentrations in muscle than controls. Conclusions: Higher uptake of [ 99m Tc]MDP in muscle of mdx mice agrees with histological reports of muscle calcification in mdx mice, and suggests the potential translational use of [ 99m Tc]MDP imaging for tracking DMD progression and therapeutic response.
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