In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.

The allele E4 of apolipoprotein E (apoE4), the most prevalent genetic risk factor for Alzheimer's disease, is associated histopathologically with elevated levels of brain amyloid. This led to the suggestion that the pathological effects of apoE4 are mediated by cross-talk interactions with amyloid ␤ peptide (A␤), which accentuate the pathological effects of the amyloid cascade. The mechanisms underlying the A␤-mediated pathological effects of apoE4 are unknown. We have shown recently that inhibition of the A␤-degrading enzyme neprilysin in brains of wild-type apoE3 and apoE4 mice results in rapid and similar elevations in their total brain A␤ levels. However, the nucleation and aggregation of A␤ in these mice were markedly affected by the apoE genotype and were specifically enhanced in the apoE4 mice. We presently used the neprilysin inhibition paradigm to analyze the neuropathological and cognitive effects that are induced by apoE4 after activation of the amyloid cascade. This revealed that apoE4 stimulates isoform specifically the degeneration of hippocampal CA1 neurons and of entorhinal and septal neurons, which is accompanied by the accumulation of intracellular A␤ and apoE and with lysosomal activation. Furthermore, these neuropathological effects are associated isoform specifically with the occurrence of pronounced cognitive deficits in the ApoE4 mice. These findings provide the first in vivo evidence regarding the cellular mechanisms underlying the pathological cross talk between apoE4 and A␤, as well as a novel model system of neurodegeneration in vivo that is uniquely suitable for studying the early stages of the amyloid cascade and the effects thereon of apoE4.

The AutoCapture (AC) function of new pacemakers (PM) from St Jude Medical (SJM) was originally recommended for use with low polarization (LP) ventricular leads only.However, recent reports have encouraged the use of the AC function with various leads, including those lacking a special LP design. The objective of this study was to analyze the reliability and safety of the AC algorithm application with different types of pacing leads. The study group comprised 30 consecutive patients with AC PMs connected to three different types of non-LP leads. Ten patients with SJM LP leads served as the control group. The study protocol included a complete AC function test using four different pulse widths (PW). The pacing threshold was independently assessed by a manual/semiautomatic check. Erratic behavior of polarization measurements with increasing PWs was demonstrated in 43% (n = 13) of the study group. Invalid polarization measurements resulted in erroneous algorithm recommendation to apply AC function in 17% (n = 5) of the study patients. Subsequent AC function activation lead to incorrect threshold determination due to missed noncapture in three patients. AC function should be applied with caution with non-LP leads. "Off label" use of these leads may cause erroneous polarization signal measurements which, in some cases, may result in incorrect pacing threshold determination, rendering a potential risk to dependent patients.