27 April 2009. The cell surface receptor p75 has earned something of a bad boy reputation among Alzheimer disease (AD) researchers. The receptor is pro-apoptotic and implicated in the death of cholinergic neurons in the AD brain. But take the receptor out of the peripheral nervous system and you’ll see its “sympathetic” side. In this week’s PNAS online, researchers led by Kuo-Fen Lee at The Salk Institute for Biological Studies, La Jolla, California, report that p75 protects peripheral sympathetic nerves against Aβ toxicity and that loss of the receptor leads to premature death in transgenic mice expressing human mutant amyloid-β (Aβ) precursor protein. The paper suggests that in some situations p75 may actually protect against Aβ. The finding could lead to new strategies for dealing with deficits in sympathetic function that occur in AD, suggest the authors.
The neurotrophin receptor p75 is a member of the tumor necrosis factor family. It is mostly expressed during development but also hangs around long after, particularly in basal forebrain neurons, which are vulnerable in AD, in the CNS. Work from Margaret Fahnestock, McMaster University, Ontario, Canada, and colleagues indicates that pro-NGF, an immature form of the nerve growth factor, might contribute to neurotoxicity in AD by activating p75 in forebrain neurons (see Peng et al., 2004). Studies in Elizabeth Coulson’s lab at the University of Queensland, Brisbane, Australia, suggest that Aβ also activates the receptor, causing the demise of neurons in the hippocampus, another vulnerable region in AD (see Sotthibundhu et al., 2008). And while there are indications that Aβ prevents the growth of sympathetic nerves as well (see Tolar et al., 1998), it is not clear if that is related to p75.
To address this possibility, Lee and colleagues tested the effect of Aβ on sympathetic neurons from the superior cervical ganglia. First author Tasha Bengoechea and colleagues found that neurite growth was the same in neurons from wild-type or p75 knockout mice, but the neurons reacted differently to Aβ42. Oligomers (made by incubating 100 μM solutions for two hours at 37 degrees) inhibited neurite growth in wild-type neurons by 40 percent; but rather than protecting from this harm, ablating p75 only made it worse. In p75-null neurons Aβ42 oligomers reduced neurite growth by a further 20 percent, suggesting that p75 actually protects sympathetic nerves against Aβ.
To see whether this matters in vivo, Bengoechea and colleagues crossed p75 knockout mice with hAPP751 transgenic mice. While the APP/p75-/- offspring appeared to develop normally in utero, about 70 percent of them died within three weeks of birth. They had profound deficits in sympathetic innervation in multiple organ systems, unlike p75 knockouts in a normal mouse APP background. The APP/p75-/- mice lost sympathetic innervation to the sweat glands of their footpads and to the ventricles of their hearts, for example. These severe defects “are consistent with the hypothesis that Aβ is able to inhibit neurite outgrowth from sympathetic neurons through p75-independent pathways, whereas p75-mediated signaling pathways are protective against Aβ-induced neurotoxicity,” write the authors. They suggest that those protective pathways may involve the p75 partner TrkA and that together they promote the survival of the neurons through NGF signaling. “This balance of Trk and p75 is critically important for the development of the nervous system, particularly the sympathetic nervous system,” said Coulson in an interview with ARF. She was not involved in this study.
That raises the question of what APP/Aβ is doing so early in the life of these animals, since these effects on the sympathetic nervous system occur well before any accumulation of Aβ is detectable. “This paper is interesting because it is a developmental system and because they can’t detect any Aβ. So they are looking perhaps at a normal function for Aβ—or APP,” said Coulson. She suggested that the absence of p75, together with the increase in APP/Aβ, might subtly change p75/TrkA signaling. Work from Dale Bredesen’s lab at the Buck Institute for Age Research, Novato, California, has recently shown that APP and p75 directly interact and alter each other’s processing, for example (see Fombonne et al., 2009).
Lee and colleagues’ contention that Aβ is the toxic factor in this system draws support from an experiment knocking out one copy of BACE—the β-secretase that is essential for amyloidogenic APP processing. “These results strongly support that sympathetic innervation deficits were due to Aβ production in the p75-deficient AD mice,” write the authors. They acknowledge that BACE has other substrates besides APP and that rescue may be partly due to other mechanisms.
While most people focus on the central nervous system when studying AD, this work is relevant to humans. As the authors point out, AD patients experience sympathetic deficits, such as a drop in blood pressure when they stand up, and it is not clear if these are due to deficits in central regulation or peripheral sympathetic innervation. “The fact that Aβ at low levels is having a physiological effect and that [Lee] can link that to human patients showing hypotension and sympathetic dysfunction is interesting. Everyone just thinks about the brain,” said Coulson.—Tom Fagan.
Bengoechea TG, Chen Z, O’Leary D, Masliah E, Lee K-F. p75 reduces beta-amyloid-induced sympathetic innervation deficits in and Alzheimer’s disease mouse model. PNAS online. 2009 April 21. Abstract