(another aricle about Dr. Mobley's research)Cause of neuronal death in Down's syndrome, Alzheimer's disease could be surprisingly simple

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Public release date: 5-Jul-2006

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Cell Press

Cause

of neuronal death in Down's syndrome, Alzheimer's disease could be surprisingly

simple

Two

papers in the July 6, 2006, Neuron, published by Cell Press, report evidence

that surprisingly simple genetic abnormalities in the machinery of critical

neuronal growth-regulating molecules can kill neurons in Down's syndrome, Alzheimer's

disease, and other neurodegenerative disorders. The researchers said their

basic findings could aid progress toward treatment for the cognitive deficits

in these disorders.

The

growth-regulating " neurotrophins " whose functional failure they studied

are taken up by neurons in sac-like carriers called " endosomes " and

transported to the main cell body, where they exert their influence.

Neurotrophins regulate neuronal development and connectivity by activating

protein switches called Trk receptors in neurons.

The two

papers were led by C. Mobley and Ahmad Salehi of Stanford University

(Salehi et al.) and G. Dorsey at the University of land Baltimore

School of Nursing and Lino Tessarollo of the National Cancer Institute (Dorsey

et al.).

In

humans, Down's syndrome is caused by a trisomy--an abnormal three copies of

chromosome 21. Such trisomy causes an increased " dosage " of genes on

that chromosome, and a central mystery of Down's syndrome is how such an

overdose of particular genes leads to such abnormalities as mental retardation.

In their

papers, Salehi and colleagues and Tessarollo and colleagues studied mice

genetically engineered to mimic the trisomy seen in human Down's syndrome.

Their aim was to discover the machinery by which this trisomy ultimately causes

the death of neurons that are important for cognitive function.

Salehi et

al. find that an increase in the expression of only one gene, for amyloid

precursor protein (APP), disrupts transport of the neurotrophin " nerve

growth factor " (NGF). APP is also a central molecule in the pathology of

Alzheimer's disease.

The

Dorsey et al. paper describes how restoring the normal cellular levels of a Trk

receptor for the neurotrophin " brain-derived neurotrophin factor "

(BDNF) rescues neuronal death in another mouse model of Down's syndrome.

Salehi et

al. found that the NGF transport disruption leads to the degeneration of

" basal forebrain cholinergic neurons " (BFCNs) important for cognitive

function. This deterioration of BFCNs is similar to that seen in Alzheimer's

disease and is caused by abnormal APP function. Since in people with Down's

syndrome, the APP gene resides on the trisomic chromosome, Salehi and

colleagues reasoned that an overdose of APP might also play a role in neuronal

degeneration in Down's syndrome and thereby contribute to cognitive deficits in

both Down's syndrome and Alzheimer's disease.

Thus, in

their studies, the researchers tested the effects of APP dosage by using three

trisomic mouse strains. One strain was trisomic on the chromosome that largely

corresponds to the one involved in human Down's syndrome. A second mouse strain

was trisomic for many of the genes, but not for APP. And a third mouse strain

was the same as the first, except that the third copy of the APP gene was

deleted.

In their

experiments, Salehi and colleagues found decreased NGF transport within the

forebrain neurons in the fully trisomic mouse, but not the ones lacking APP

trisomy. And, in studies of mice with different doses of the APP gene, they

found that the greater the APP dose, the worse the NGF transport. What's more,

the researchers' analysis of NGF-carrying endosomes in the affected neurons

yielded evidence that the APP protein overloaded those endosomes, decreasing

NGF transport.

Salehi

and colleagues concluded that " In pointing to the importance of gene dose

and overexpression of a specific gene in the setting of trisomy, the current

study is expected to enhance progress in understanding the cellular mechanism

of pathogenesis for neurodegeneration in DS. It makes the argument that even in

the context of a complex genetic lesion, increased dose for but one gene can

impact important features of neuronal structure and function. Though other

genes in the trisomic segment must contribute to the defect in NGF transport

and to degenerative changes, our report draws attention to a surprisingly

robust effect of the dose for App. "

The

researchers also wrote that " increased gene dose for APP may contribute

significantly to the pathogenesis of AD-related changes and dementia in people

with DS, including the degeneration of BFCNs. If so, treatments to reduce APP

gene expression may prove valuable. "

The paper

by Tessarollo and colleagues explored the mechanism of neuronal cell death in

another trisomic mouse model. In previous studies, they had found that trisomy

causes an overproduction of a truncated version, or " isoform, " of a

Trk neurotrophin receptor. This overproduction compromises BDNF function and

causes the death of neurons in the hippocampus, they found. The hippocampus is

a major center in the brain for learning and memory. The researchers also found

in their previous work that they could restore survival of these neurons by overexpressing

the full-length Trk receptor.

In the

new Neuron paper, Tessarollo and colleagues found that they could also prevent

neuronal cell death by genetic manipulation to reduce the truncated Trk

receptor to normal levels.

The

researchers concluded that " Our results suggest that alterations of

receptor isoform expression can affect neurotrophin signaling and consequently

neuron survival. " " Small alterations in neurotrophin/Trk receptor

activation like those seen in [the trisomic mouse model] may be directly linked

to neurodegenerative diseases. "

Tessarollo

and colleagues also noted that " Alterations in neurotrophins or their Trk

receptor levels have been reported in a variety of neurodegenerative diseases,

including amyotrophic lateral sclerosis (ALS) and Alzheimer's, Huntington's,

and Parkinson's diseases. However, it is still unclear whether changes in

expression of these receptors are involved in the pathogenic process or are an

indirect effect of the disease. "

A lack of

good animal models had prevented scientists from exploring the effects of Trk

receptor abnormalities on neuronal cell death, wrote Tessarollo and colleagues.

However, they wrote, their trisomic mouse strain has enabled such studies, with

surprising results.

" The

cause of the accelerated cell death has the potential to be multigenic, since

hundreds of genes are dysregulated in trisomies, " they wrote.

" Surprisingly, we have found that an alteration in TrkB receptor signaling

is sufficient for the development of this phenotype, suggesting that

dysregulation of a single gene is sufficient to cause cellular alterations

resulting in neuron death. "

In a

preview of the two papers, Eero Castrén and Heikki Tanila of the University of

Helsinki wrote in the same issue of Neuron " Although the results of these

studies are still far from suggesting any new therapeutic strategies for Down's

syndrome, it might be possible that drugs influencing APP processing could in

the future help to restore the retrograde transport of NGF and thereby

cognitive symptoms in Down's syndrome. In any case, the papers provide

interesting insights into the pathophysiology of Down's syndrome and underline

the notion that the primary aim of treatment of neurodegenerative disorders is

not to keep neurons alive but to keep them connected. "

(Salehi

et al.)

The

researchers include Ahmad Salehi, Pavel V. Belichenko, Ke Zhan, Chengbiao Wu,

Janice S. Valletta, Ryoko Takimoto-Kimura, M. Kleschevnikov and

C. Mobley of Stanford University in Stanford, CA; Jean-Dominique Delcroix

of Stanford University in Stanford, CA and the European Brain Research

Institute, Rita Levi-Montalcini Foundation in Rome, Italy; Kumar Sambamurti and

P. Chung of the Medical University of South Carolina in ton, SC;

Weiming Xia and A. of Harvard Medical School in Boston, MA;

Villar, J. Epstein, of University of California, San Francisco

in San Francisco, CA; Shapiro Kulnane and Bruce T. Lamb of Case Western

Reserve University in Cleveland, OH; Ralph A. Nixon of Kline Institute

in Orangeburg, NY; Gorazd B. Stokin and Lawrence S.B. Goldstein of University

of California, San Diego in La Jolla, CA; of Stanford University and Stanford

University School of Medicine in Stanford, CA.

This

research was sponsored by grants from the NIA (AG16999, W.C.M.), NINDS

(NS38869, W.C.M.), NICHD (31498, C.J.E.), Adler Foundation (J.D.D.), Alzheimer

Association and State of California Alzheimer's Program (A.S. and W.C.M.),

McGowan Charitable Trust, Larry L. Hillblom Foundation, and the Down Syndrome Research and Treatment Foundation

(W.C.M.).

(Dorsey

et al.)

The

researchers include G. Dorsey of the University of land School of

Nursing in Baltimore, MD (formerly of the National Cancer Institute in

Frederick, MD); Renn and W. Ward of the University of

land School of Nursing in Baltimore, MD; Bambrick and Bruce K.

Krueger of the University of land, Baltimore School of Medicine in

Baltimore, MD; Carim-Todd, Colleen A. Barrick, and Lino Tessarollo of the

National Cancer Institute in Frederick, MD.

###

This

research was supported by the Intramural Research Program of the NIH, National

Cancer Institute, Center for Cancer Research; NIH grants K22NR00174-03

(S.G.D.), R01NS40492 (B.K.K.), and K01-AR02177 (C.W.W.).

Salehi et

al.: " Increased App Expression in a Mouse Model of Down's Syndrome

Disrupts NGF Transport and Causes Cholinergic Neuron Degeneration. " www.neuron.org

Dorsey et

al.: " In Vivo Restoration of Physiological Levels of Truncated TrkB.T1

Receptor Rescues Neuronal Cell Death in a Trisomic Mouse Model. " www.neuron.org

Related

Preview by Castrén et al.: " Neurotrophins and Dementia--Keeping in Touch. "