"Up to now, none of the APP transgenic mice we have has consistently shown significant neurodegeneration," said Donna Wilcock of the University of Kentucky, who was not involved in the research. She added that neurodegeneration is a critical component of the Alzheimer's process. Scientists, including senior investigator Leonardo Belluscio of the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland, know that the olfactory system is among the first to succumb to the ill effects of Alzheimer's disease (AD) (see Bacon et al., 1998), and that amyloid pathology in the olfactory epithelium (OE) parallels brain pathology (see ARF related news story on Wesson et al., 2010; Arnold et al., 2010). They hypothesized that olfactory sensory neurons (OSNs), which detect scent information in the nasal cavity and send it to the brain's olfactory bulb, were more vulnerable to AD pathology than cortical cells, and might make a good model to study APP-induced neurodegeneration. Belluscio and colleagues generated two mouse lines: one that expressed human APP (hAPP) in mature OSNs; and one that expressed the protein in immature OSNs, each driven by promoters specific to those cell types.

When the mice were just three weeks old, the team saw four times as much apoptosis in hAPP-expressing cells as in controls, as evidenced by the presence of cleaved caspase-3 and TUNEL staining. Cell death occurred only in those subsets of cells that produced hAPP, leaving healthy neighboring cells unaffected. Immunoelectron microscopy turned up no evidence of Aβ plaques. In addition, hAPP-producing mature cells were more likely to be apoptotic than hAPP-positive immature neurons. This could mean mature cells may be more susceptible to hAPP's effects, the authors wrote.

"Trying to determine the basis of vulnerability [in the olfactory sensory neurons] may also give us insight as to why certain other brain regions are susceptible," Belluscio said.

The team, which included first author Ning Cheng of NINDS and Huaibin Cai of the National Institute on Aging, was able to control the expression of hAPP via the tetracycline-(tet-off)-transactivation system. Feeding the mice doxycycline halted hAPP expression within a week. The measure rescued hAPP-positive immature neurons, leaving significantly more proliferating cells and fewer apoptotic cells in the olfactory epithelium. But hAPP-producing mature cells weren't so lucky; the rescue only modestly improved cell survival. "We're quite interested in trying to understand what might be the basis for that difference," said Belluscio.

Along with hippocampal cells, neurons in the olfactory epithelium are among the first to suffer in the early stages of AD and other neurological disorders. Both regions are characterized by a relatively high cell turnover, which the authors suggest could be a contributing factor to their APP susceptibility.

"We really don't have a clue for why the olfactory system is so sensitive to many different disorders," said Donald Wilson of the New York University School of Medicine and the Nathan Kline Institute for Psychiatric Research, who added that much of the research has focused on more central structures. "It's nice that this paper emphasizes that these cells, at least in this model system, are very sensitive to APP."

The study does not resolve the controversy about whether Aβ plaques are a cause or effect in AD, or both. It suggests Aβ plaques are not necessary for neurodegeneration, but it falls short of pinpointing an exact mechanism for cell death. Soluble forms of Aβ, which many researchers believe are the most toxic, could be to blame (see ARF related news story on McDonald et al., 2010). The researchers note that in the olfactory epithelium of both mouse lines, levels of Aβ40 and Aβ42 were dramatically higher than in wild-type mice. Other research suggests, for example, that an extracellular domain of APP causes neuron loss via a "death receptor," which sets off an apoptotic cascade (see ARF related news story on Nikolaev et al., 2009). This new mouse model, which exhibits neurodegeneration relatively early in a specific set of cells that are readily accessible through the nose, may allow researchers to answer questions that might be harder to address by studying deeper brain regions, said Belluscio. Because the gene expression can be turned on and off, researchers can explore, for instance, whether APP causes lasting damage. In addition, he said, the model will shed light on this oft-overlooked brain region in AD.

"Because there's been so much focus on the cognitive dysfunctions that go along with these disorders, many other areas may actually have been neglected that could give important insight," Belluscio said.—Gwyneth Dickey Zakaib.

Reference:
Cheng N, Cai H, Belluscio L. In Vivo Olfactory Model of APP-Induced Neurodegeneration reveals a reversible cell-autonomous function. J. Neurosci. 2011 Sep 28; 31(39):13699-13704. Abstract