16 Jul 2010

The protein reelin helps rein in pathology in Alzheimer disease mice, according to a recent report which comes on the heels of related findings presented at “ApoE and ApoE Receptors in Neurodegeneration,” a one-day symposium held 7 June 2010 in St. Louis, Missouri. At that meeting, Edwin Weeber, University of South Florida, Tampa, reported that reelin restores synaptic plasticity in hippocampal slices from amyloid precursor protein (APP) transgenic mice, while Joachim Herz, University of Texas Southwest Medical Center, Dallas, outlined how the protein rescues Aβ toxicity in an ApoE isoform-dependent manner. Reelin, an ApoE receptor ligand, restores long-term potentiation in Aβ-treated hippocampal slices if they have an ApoE2 or ApoE3 background, but not in ApoE4-positive tissue (see ARF related news story).

Now, the new work, described in the July 7 Journal of Neuroscience, reinforces the reelin connection. Researchers led by Irene Knuesel at the University of Zurich, Switzerland, report that Aβ and tau pathology are amplified when transgenic APP695 mice are crossed with reeler (reln) mice, which lack one copy of the reelin gene. Joint first authors Samira Kocherans and Amrita Madhusudan and colleagues found that Aβ plaques appear in App/reln mice as early as six months of age, three months before they emerge in the APP parent strain. Furthermore, the density of large plaques in the hippocampus and cerebral cortex was greater in nine-month-old APP/reln crosses than age-matched APP controls. The authors attribute the early and exacerbated plaque pathology to more rampant amyloidogenic processing of APP, since they detected much more soluble Aβ40/42 and more β-secretase-derived C-terminal APP fragments in the hippocampus and cortex of the APP/reln mice.

The lack of reelin had further reaching effects, including activation of microglia and astrocytes and elevation of tau phosphorylation. Tau phosphorylation was particularly evident in the vicinity of Aβ plaques in 15-month-old APP/reln mice. In these aged animals, the authors also found evidence of dystrophic neurites and neurofibrillary tangles, which are generally not found in APP transgenic mice. “Together, the findings indicate that a genetic reduction in reelin expression accelerates the production of amyloidogenic Aβ peptides, which results in earlier plaque formation and an age-related aggravation of the pathology, including early signs of neurodegeneration...,” write the authors. Given that reelin also rescues the inhibitory effects of Aβ on synaptic plasticity, as described at the St. Louis meeting, it appears that the protein not only retards production of Aβ, but its toxicity as well, which makes it an interesting candidate for further study.—Tom Fagan