Nathalie Chevallier

Modulation of amyloid β-protein clearance and Alzheimer’s disease susceptibility by the LDL receptor–related protein pathway

Susceptibility to Alzheimers disease (AD) is governed by multiple genetic factors. Remarkably, the LDL receptor-related protein (LRP) and its ligands, apoE and alpha2M, are all genetically associated with AD. In this study, we provide evidence for the involvement of the LRP pathway in amyloid deposition through sequestration and removal of soluble amyloid beta-protein (Abeta). We demonstrate in vitro that LRP mediates the clearance of both Abeta40 and Abeta42 through a bona fide receptor-mediated uptake mechanism. In vivo, reduced LRP expression is associated with LRP genotypes and is correlated with enhanced soluble Abeta levels and amyloid deposition. Although LRP has been proposed to be a clearance pathway for Abeta, this work provides the first in vivo evidence that the LRP pathway may modulate Abeta deposition and AD susceptibility by regulating the removal of soluble Abeta.

Perturbed neurogenesis in the adult hippocampus associated with presenilin-1 A246E mutation.

In addition to its well-established role in gamma-secretase cleavage, presenilin (PS) also plays a role in regulating the stability of cytosolic beta-catenin, a protein involved in Wnt signaling. Several familial Alzheimers disease-associated PS1 mutations have been shown to increase the stability of the signaling pool of beta-catenin, correlating with enhanced cell proliferation. Accordingly, we hypothesized that in the setting of PS1 mutations, abnormal activation of Wnt/beta-catenin signaling leads to increased cell division. We tested this hypothesis by examining whether there is evidence of increased neurogenesis in the hippocampus of adult transgenic mice that overexpress the PS1 A246E mutation. In PS1/PS2-deficient fibroblasts, expression of PS1 A246E Familial AD mutation failed to restore the rapid turnover of beta-catenin compared with wild-type PS1. We then examined whether the same mutation enhanced neurogenesis in vivo in adult hippocampus of PS1-deficient mice when restored by wild-type human PS1 (PS1(-/-)WT) or A246E PS1 mutation (PS1(-/-)AE). The PS1 A246E mutation stimulated the proliferation of progenitor cells in the dentate gyrus of adult mice, as assessed by 5-bromo-2-deoxyuridine incorporation, but did not influence their survival or differentiation. These observations suggest that the PS1 A246E mutation influences cell growth putatively via abnormal beta-catenin signaling in vivo.

Deficiency in either COX-1 or COX-2 genes does not affect amyloid beta protein burden in amyloid precursor protein transgenic mice

Epidemiologic studies indicate that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a lower risk for developing Alzheimers disease (AD). Because the primary mode of action of NSAIDs is to inhibit cyclooxygenase (COX) activity, it has been proposed that perturbed activity of COX-1 or COX-2 contributes to AD pathogenesis. To test the role of COX-1 or COX-2 in amyloid deposition and amyloid-associated inflammatory changes, we examined amyloid precursor protein (APP) transgenic mice in the context of either COX-1 or COX-2 deficiency. Our studies showed that loss of either COX-1 or COX-2 gene did not alter amyloid burden in brains of the APP transgenic mice. However, one marker of microglial activation (CD45) was decreased in brains of COX-1 deficient/APP animals and showed a strong trend in reduction in COX-2 deficient/APP animals. These results suggest that COX activity and amyloid deposition in brain are likely independent processes. Further, if NSAIDs do causally reduce the risks of AD, then our findings indicate that the mechanisms are likely not due primarily to their inhibition on COX or γ-secretase modulation activity, the latter reported recently after acute dosing of ibuprofen in humans and nonhuman primates.