22 May 2009. The oldest and the youngest people are often the most vulnerable to disease. The same might be true for cells. Alzheimer disease (AD) primarily attacks those aged 65 and older, robbing them of their 65-year-old neurons—and their memories. But immature neurons might also be at risk in AD, according to a paper in this week’s Journal of Neuroscience. Ping He and senior author Yong Shen, both at Sun Health Research Institute, Sun City, Arizona, report that brain neuronal progenitors isolated from Alzheimer patients have trouble making new neurons. “We found that proliferation is fine but progenitor cells isolated from AD brain cannot differentiate into neurons,” Shen told ARF. The researchers traced the problem to amyloid-β (Aβ), which seems to block cellular signals that are essential for neurogenesis. “It is not only that neurons are degenerating in AD, but neural progenitors are suffering too,” said Shen.
Neurogenesis in the adult human brain is extremely limited. Nonetheless, recent evidence suggests that adult-born neurons can significantly contribute to function, playing roles in memory formation (see ARF related news story on Trouche et al., 2009) and even in the action of some anti-depressants (see ARF related news story). Some researchers hope that neurogenesis, either natural or from transplanted stem cells, might one day offer a way to treat neurodegenerative diseases such as AD and Parkinson’s. But Shen’s work suggests that might not be so straightforward. “There may be a pathological environment in the Alzheimer’s brain that is not suitable for stem cells. What’s more, signal transduction pathways are interrupted, and that’s not good either,” he told ARF.
Shen and He identified the neurogenesis problem when studying precursor cells from AD and age-matched healthy control brains. From the cerebral cortex they isolated glial precursor cells (GPCs), which can give rise to the three major cell types of the brain—neurons, glia, and oligodendrocytes. The researchers found that when grown in culture, GPCs from AD autopsy tissue made significantly fewer neurons than the same cells isolated from healthy tissue. GPCs and their progeny also made more Aβ40/42 than control cells, suggesting that the peptide might somehow prevent progenitors from forming neurons. To test this idea, He incubated GPCs from healthy brain with aggregates of Aβ (the peptide was incubated overnight). The treatment induced apoptosis, or programmed cell death, in cells that began to express neuron or oligodendrocyte markers, suggesting that Aβ is toxic to these fledgling cell types. In contrast, the peptide seemed to have no effect on cells differentiating toward glia. “That may help explain why there is gliosis, or activated glial cells, in the AD brain,” said Shen.
The progeny of GPC cells isolated from AD brain also had reduced expression of proneuronal genes, such as neurogenin 2 (Ngn2) and neurogenic differentiation factor 1, suggesting that pro-neuronal signals are suppressed in those cells. Since Wnt/β-catenin signaling is a major driving force in adult neurogenesis (see ARF related news story
on Lie et al., 2005), He looked to see if this pathway is perturbed in progenitors from AD brain. He found that levels of Wnt and its receptor Frizzled appeared normal, but that the dynamics of β-catenin, a major downstream transcription factor, were far from it. The level of active β-catenin was significantly lower in GPCs from AD brain (and their progeny) compared to cells from normal healthy brains. In contrast, levels of inactive phosphorylated β-catenin, and its kinase, GSK-3β, were much higher than in control cells. Transfecting AD GPCs with β-catenin restored proneuronal gene expression, while silencing β-catenin in normal healthy GPCs had the opposite effect, confirming the pivotal role played by this transcription factor. Furthermore, by treating GPCs from healthy controls with Aβ aggregates, He was able to evoke an AD GPC-type expression profile, with elevated GSK-3β and phosphorylation of β-catenin, again suggesting that the peptide is bad news for neuronal differentiation. The authors also found that neurogenesis from GPCs is perturbed in APP23 transgenic mice, which overexpress Aβ, and that β-catenin signaling is attenuated in mouse progenitors as in GPCs from human AD brain. All told, the results suggest that the Aβ in the AD brain may create a noxious environment for adult neurogenesis.
This is not the first time AD has been linked to neurogenesis. Notch signaling, which requires the same presenilin that processes Aβ precursor protein (APP), helps drive adult neurogenesis (see ARF related news story on Breunig et al., 2007). Presenilin mutations may suppress it (see ARF related news story on Wen et al., 2004) even when driven by environmental enrichment (see ARF related news story), a known promoter of neurogenesis in mammals. The results also tie in with previous findings showing that mutant forms of presenilin destabilize β-catenin (see ARF related news story) and that APP signaling can suppress neurogenesis (see ARF related news story on Ma et al., 2008) .
Whether any of these APP/PS effects are solely due to production of Aβ is unclear, said Shen. He plans to study signal transduction in neural progenitors to see how it relates to APP signaling and whether tweaking various signaling pathways might help improve adult neurogenesis. In this regard, some advances have been made with embryonic stem cells. Small molecules that activate GSK-3β have been shown to activate neurogenesis, for example (see ARF related news story), and in the May 17 Nature Neuroscience online, researchers led by Freda Miller at the Hospital for Sick Children, Toronto, Canada, report on two factors that regulate neurogenesis in mouse embryonic cortical precursors. First author Andree Gauthier-Fisher and colleagues found that knocking down Lfc, a guanine nucleotide exchange factor, blocks neurogenesis, while knocking down the Lfc negative regulator Tctex-1, on the contrary boosts neurogenesis. Unlike Aβ, which seems to act on the differentiation phase of neurogenesis, Lfc seems to work on the proliferative phase, helping to orient the mitotic spindles that are necessary for cell division.—Tom Fagan.
He P, Shen Y. Interruption of beta-catenin signaling reduces neurogenesis in Alzheimer’s disease. J. Neurosci. 2009 May 20; 29:6545-6557. Abstract
Gauthier-Fisher A, Lin DC, Greeve M, Kaplan DR, Rottapel R, Miller FD. Lfc and Tctex-1 regulate the genesis of neurons from cortical precursor cells. Nature Neuruscoience. 2009 May 17 online. Abstract