In This Issue
DEVELOPMENTAL BIOLOGY
Scaling up stem cells
The devastating neurological effects of Parkinson's disease are the manifestation of dying dopaminergic neurons. Large-scale production of dopaminergic neurons from human embryonic stem (hES) cells, reported by Myung Soo Cho et al., could open the door for new clinical therapies. When dopamine-producing cells die, synthetic dopamine can stand in for a time, but the treatment loses effectiveness and side effects accumulate. Cell therapy using hES cells could replenish dopaminergic neurons. Cho et al.'s technique, which generated spherical neural masses, produced >77% neurons in as little as 14 days. Strikingly, ≈86% of the neurons were dopaminergic neurons. This high level of purity and lack of feeder cells decrease the risk of complications once implanted. The authors also demonstrated that the hES-derived dopaminergic neurons improved behavioral symptoms in a rat model of Parkinson's disease. By overcoming technical limitations in derivation of dopaminergic neurons from hES cells and addressing efficacy questions of differentiated dopaminergic neurons, the authors suggest that their work provides a good basis for future treatment of Parkinson's disease with stem cells. — T.H.D.
Coronal sections of rat brain showing treated (Left) and untreated (Right) embryonic stem cells.
“Highly efficient and large-scale generation of functional dopamine neurons from human embryonic stem cells” by Myung Soo Cho, Young-Eun Lee, Ji Young Kim, Seungsoo Chung, Yoon Hee Cho, Dae-Sung Kim, Sang-Moon Kang, Haksup Lee, Myung-Hwa Kim, Jeong-Hoon Kim, Joong Woo Leem, Sun Kyung Oh, Young Min Choi, Dong-Youn Hwang, Jin Woo Chang, and Dong-Wook Kim (see pages 3392–3397)
GENETICS
Closing the circle of longevity
In laboratory animals, from flies to worms to mice, the insulin-like growth factor (IGF-I) pathway is implicated in longevity. IGF-I levels are strongly linked to body size. In mammalian animal models, decreased levels of IGF-I predispose for short stature, but also increase longevity. To determine whether IGF-I plays a role in human longevity, Yousin Suh et al. looked for genetic variations in a cohort of Ashkenazi Jewish centenarians and their offspring. The authors used another group of Ashkenazi individuals with no history of familial longevity as controls. Comparing the two groups, the authors found that, although the IGF-I coding region was highly conserved, centenarians and their offspring were more likely to have a variety of mutations in the IGF-I receptor. The mutations, which led to a mild form of IGF-insensitivity, were more apparent in females and led to shorter stature in the offspring. The work shows that, even though specific mutations were relatively rare, those affecting the IGF-I signaling pathway play a role in human longevity. — T.H.D.
Position of mutated amino acids in IGF-I.
“Functionally significant insulin-like growth factor I receptor mutations in centenarians” by Yousin Suh, Gil Atzmon, Mi-Ook Cho, David Hwang, Bingrong Liu, Daniel J. Leahy, Nir Barzilai, and Pinchas Cohen (see pages 3438–3442)
MICROBIOLOGY
Viral encephalitis treated by glutamate-receptor antagonists
Often transmitted by mosquitoes, viruses that cause encephalitis have emerged as a growing threat around the world. Cases of eastern equine encephalitis (EEE), a type of single-stranded RNA alphavirus, are on the rise: In 2005, the United States reported the largest number of cases of the illness, which has a 35% mortality rate, since 1964.From a molecular standpoint, viral encephalitis can cause disease through damage to neurons by viral replication, toxicity from overproduction of the neurotransmitter glutamate, and damage from the immune response to the invading pathogen. Therapeutics, such as talampanel, that block the activation of AMPA-type glutamate receptors can prevent neurotoxicity, although the mechanism for this protection has not been well understood. Ivorlyne Greene et al. studied the effects of talampanel on viral encephalitis in mice. The authors infected the animals with a neurovirulent strain of the Sindbis virus (NSV), an alphavirus related to EEE that causes fatal encephalomyelitis associated with motor neuron death. The authors found that talampanel-treated mice could not activate immune cells in secondary lymphoid tissue in response to infection. Although viral titers remained high in these animals, the mice experienced no immune-mediated damage or glutamate-toxicity and, thus, no paralysis. The results demonstrate the usefulness of AMPA receptor antagonists to treat viral encephalitis, according to the authors. — F.A.
NSV protein in mice 7 days after intercerebral infection.
“Protection from fatal viral encephalomyelitis: AMPA receptor antagonists have a direct effect on the inflammatory response to infection” by Ivorlyne P. Greene, Eun-Young Lee, Natalie Prow, Brownhilda Ngwang, and Diane E. Griffin (see pages 3575–3580)
NEUROSCIENCE
Altered blood vessel architecture in Alzheimer's brains
Imaging blood vessel architecture in the brain or scanning for altered blood flow may allow early diagnosis of Alzheimer's disease. Previous studies have shown that changes to blood vessel architecture are rampant in older transgenic APP23 mice, the animal model of Alzheimer's disease. Furthermore, decreased blood flow to the brain is a consistent feature in Alzheimer's patients. It is not clear, however, whether these changes are a result of neuronal damage or the cause. Eric Meyer et al. created 3D casts of the blood vessels from the brains of APP23 mice and used scanning electron microscopy to produce a high-resolution snapshot of the vasculature. The authors found that, early in the disease, before the hallmark amyloid plaques are visible, dramatic change occurs in the microvasculature. Associated with these abnormal vessels are tiny plaques. Meyer et al. suggest that deposits of β-amyloid protein on vessels accelerate plaque accumulation that further degrades blood vessels. As these structures degenerate, they leave holes, which are seen in older animals. The authors hypothesize that blood vessel loss promotes new blood vessel formation, altering the blood flow and potentially wreaking havoc on memory and learning processes. — B.T.
“Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer's disease” by Eric P. Meyer, Alexandra Ulmann-Schuler, Matthias Staufenbiel, and Thomas Krucker (see pages 3587–3592)
