Newsdesk

298 http://neurology.thelancet.com Vol 5 April 2006

Immune cells from blood attack Alzheimer’s plaques

Potassium channels have a critical role in various physiological processes, and have been described in episodic neurological diseases. Researchers now report that potassium channel mutations can cause disease phenotypes with neurodevelopmental and neurodegenerative features.

“Our key fi nding is that this is the fi rst time that this particular channel mutation has been linked to neuro-degeneration”, says lead researcher Stefan Pulst (University of California,

Los Angeles, USA). “These abnorm-alities may be associated with a wide variety of neurodegenerative diseases including Alzheimer’s and Parkinson’s.”

Spinocerebellar ataxias (SCAs) aff ect the brain and spinal cord causing progressive diffi culty with coordination. Of 26 SCAs that have been described, the causative gene or mutation is known for ten of them. A mutation in the KCNC3 gene has been mapped in a large French family with a

history of SCA13, which causes a slowly progressive cerebellar gait ataxia with a childhood onset, cerebellar degen-eration, and mild mental retardation.

In this study, Pulst and colleagues looked at three generations of a Filipino family segregating a dominant trait for cerebellar ataxia. They identifi ed KCNC3 mutations as the cause of SCA13 ataxia in the Filipino family, but cell cultures revealed that the respective mutations manifested quite diff erently in the two family lineages. In the French

Potassium channels have a key role in neurodegeneration

A new study using a mouse model of Alzheimer’s disease (AD) shows that circulating immune macrophages enter the brain to seek out and destroy the toxic amyloid plaques that are a hallmark of the disease (Neuron 2006; 49: 489–502). Attracted by the amyloid protein itself, the macrophages could represent a natural immune defense against the disease.

If similar results are obtained in people, then boosting the activity of the macrophages could be a promising new approach to treating AD, suggests study investigator Serge Rivest (Laval University, Quebec, Canada).

The brain infi ltrating cells, and the blood stem cells that give rise to them, could be ideal targeting vehicles to

deliver plaque-busting enzymes, anti-bodies, or gene therapies to the CNS.

Two other groups have indepen-dently identifi ed brain invasion by bone-marrow-derived immune cells in mouse models of AD using transplantion of green fl uorescent protein-labelled bone-marrow stem cells in mice genetically engineered to develop AD-like amyloid plaques. In all cases, signifi cantly more GFP-labelled immune cells infi ltrated brains of mice with plaques than of those without. In the AD mice, the invading cells cluster around and reach into the core of the plaques, similar to the brain’s own resident immune cells, the microglia.

The new study shows that the lure for the cells is the toxic amyloid beta (Aβ) peptide. Direct injection of amyloidogenic peptides of Aβ, but not harmless ones, into mouse brains resulted in recruitment of Aβ-reactive peripheral cells to the site of injection.

The newly arrived cells seemed to be gobbling up Aβ from the plaques. To try to distinguish the activity of resident versus imported cells, Rivest and colleagues developed a transgenic mouse in which they could selectively deplete bone-marrow-derived cells while leaving resident microglia intact. Plaque abundance and size increased when the infi ltrating cells were reduced.

The loss of plaque will mean little if the mice do not show gains in neuron survival, synaptic function, and cognitive improvement. Those experi-ments are critical to judging the value of the observations, says Joseph Rogers (Sun Health Research Institute, Sun City, AZ, USA). “Many of us had not thought very much about peripheral macrophages being that much involved, but this paper makes clear that at least in transgenic mice they can be. These are groundbreaking, but very preliminary data.”

To boost the benefi cial eff ects of blood-derived phagocytes, blood stem cells could be genetically tailored to more strongly recognise amyloid, or to carry amyloid-degrading enzymes to aff ected brain tissues. Mathias Jucker (University of Tuebingen, Germany) says: “If you think about it, the blood cells are a good vehicle—in normal brain they go in a little bit, but if you have amyloid they go in much more, and then specifi cally go to the plaques. What more could you want?” Jucker, whose own laboratory recently showed the homing of peripheral monocytes and T cells to the brain in a mouse model of AD, says the theory is great, but only time will tell if the current work will translate into a realistic treatment.

Pat McCaff rey

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Microglia aggregate around Aβ plaques in AD

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Newsdesk

http://neurology.thelancet.com Vol 5 April 2006 299

family, the mutation created a malfunction in the potassium channels, causing them to open earlier than normal and close too late. Conversely, in the Filipino family, the mutation prevented the potassium channel from functioning at all (Nat Genet 2006; published online Feb 26. DOI:10.1038/ng1758).

The KCNC3 gene encodes the voltage-gated Shaw channel, which is important for the properties of bursting neurons. Alterations occur in the expression patterns of potassium channels in Huntington’s, Parkinson’s, and Alzheimer’s disease, and neuro-

physiological studies of bursting neurons have implicated voltage-gated potassium channels in human neurodegenerative diseases.

The results of this study show that mutations in the KCN3 channels are suffi cient to cause neurodegeneration, and the researchers suggest that these channels be assessed as mutational and therapeutic targets in bursting neurons in the hippocampus and substantia nigra in conjunction with diseases such as Alzheimer’s.

“The current paradigm is heavily focused on looking at folded proteins”, says Pulst. “This opens up a whole

new class of proteins that can cause neurodegenerative disease or con-tribute to it.”

These fi ndings are likely to stimulate the search for additional mutations in the KCNC3 gene, comments Bernardo Rudy (New York University, NY, USA). “The two mutations found so far occurred in amino acid positions that were already known to be functionally important. It is likely that new mutations will be discovered that will highlight domains of Kv3.3 channels that have not been a focus of interest.”

Roxanne Nelson

Ghrelin is known to aff ect pituitary hormone secretion, appetite, meta-bolism, gastrointenstinal function, and the cardiovascular and immune systems. Now, a team of researchers led by Tamas Horvath (Yale University School of Medicine, CT, USA) reveal an endogenous function of ghrelin that links metabolic control with spatial learning and memory.

Neuronal plasticity within the hippocampal formation has been associated with spatial learning and memory development. Together with the observation that growth hormone secretagogue receptors, or ghrelin receptors, are present in the hippocampal formation, this information “raised the question of whether ghrelin would bind and enter the hippocampus, and whether its presence there indicates that it has a physiologic role in altering neuronal morphology and associated hippo-campal functions”, explains Horvath. Although the eff ect of ghrelin on memory performance has been suggested before, “the authors have extended these data about the eff ect of ghrelin on memory using diff erent experimental approaches”, Susana R de Barioglio (Universidad Nacional de Córdoba, Córdoba, Argentina) told The Lancet Neurology.

Horvath and colleagues analysed the presence of radiolabelled human ghrelin in various parts of mouse brains after peripheral injection. “Our results revealed that circulating ghrelin enters the hippocampal formation”, says Horvath. Furthermore, the distribution of labelled cells and processes suggested that ghrelin binds to processes of hippocampal neurons.

The researchers analysed hippocam-pal tissue from animals that received peripheral administration of either synthetic ghrelin or saline. Assessment of the density of axospinal synapses in the CA1 region of the hippocampus showed that spine synapse density was signifi cantly higher in ghrelin-treated animals than in controls.

In parallel with the changes in synapse number and increased ghrelin concentrations, various behavioural tests known to be dependent, at least in part, on the hippocampus showed enhanced performance of the animals. Horvath’s team used ghrelin-knockout mice to confi rm these data. Mice that lacked ghrelin had fewer spine synapses and underperformed in novel object recognition tests compared with their wild-type littermates. However, ghrelin administration rapidly restored this impairment, indicating that the hormone aff ects

neuronal morphology of brain areas known to be responsible for learning performance and memory function.

These fi ndings “raise the possibility of therapeutic uses of the peptide or its agonists in neurological diseases”, suggests de Barioglio. For example, orally active ghrelin analogues could off er a potential treatment for impaired learning and memory processing that occurs in association with ageing and neurological disorders such as Alzheimer’s disease.

Laura Thomas

An appetite for learning

Ghrelin-like drugs could protect against dementia

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