News & Views Archives

Issue No. 7, Summer 2006

We are happy to announce that the long awaited Down Syndrome Clinic at Stanford will open its doors on July 11th. The clinic is located in the Lucile Packard Children’s hospital. To make an appointment, please call the clinical coordinator at (650) 723-6858, extension 1. For more information visit our clinic web page.

Dr. Salehi and colleagues from Stanford and from several other national universities have recently identified a gene whose increased levels lead to neurodegeneration in Down syndrome. These exciting research findings have been published in the July 6th issue of the journal Neuron. The abstract of the paper can also be viewed here. The details of these findings and their significance are discussed below.

In the spotlight

An extra copy of the App gene causes degeneration of brain cells in a Down syndrome mouse model
By Sietske Heyn, Ph.D.

The brain of virtually every person with Down syndrome older than 40 years shows neurodegeneration identical to Alzheimer’s disease (AD) (1). With increasing age, increasing neurodegeneration causes many people with Down syndrome to suffer from cognitive decline (2). To date, the mechanisms underlying this neurodegeneration and how it causes cognitive decline are poorly understood. We only know that, somehow, having an extra copy of one or several genes on chromosome 21 must be responsible.

Most people with Down syndrome have a complete extra copy of chromosome 21, containing at least 300 genes (3). One of the challenging tasks for scientists is to tease out, which of these 300 genes contribute(s) to the cognitive decline found in people with Down syndrome. In a recent issue of the journal Neuron, Dr. Salehi and colleagues from the Stanford University Center for Research and Treatment of Down Syndrome published findings that may shed some light on this question.

Basal forebrain cholinergic neurons (BFCNs) are a group of brain cells that are important for attention, learning and memory functions. BFCNs receive input from a protein produced in the hippocampus, called nerve growth factor (NGF). NGF plays a vital role in the well-being of BFCNs. Once NGF is secreted by hippocampal cells, it binds to specific receptors located at the synapses of BFCNs (See Figure 1). NGF and its receptor then become enclosed in a vesicle called signaling endosome and travel from the synapse, through the axon all the way back to the cell body and nucleus (4). At the nucleus, the signaling endosome triggers a complex cascade of events, involving changes in the expression levels of specific genes. The products of these genes are necessary for maintaining normal function of BFCNs, including their synapses – the points of communication between brain cells.

Figure 1. Diagram showing retrograde transport of NGF (in red). NGF is released from the hippocampal neuron and binds to its receptor on the basal forebrain cholinergic neuron (BFCN). NGF and its receptor are enclosed in a signaling endosome. The signaling endosome travels to the cell body and nucleus of the BFCN, where NGF triggers a complex cascade of events that ensures proper cell maintenance and function.

Under conditions where NGF transport to the nucleus is blocked in BFCNs, insufficient signaling messages are transmitted to the cells. The BFCNs are unable to express the proper amount of genes and their protein products necessary for normal cell maintenance and function (See Figure 2). BFCNs degenerate and stop producing acetylcholine – a neurotransmitter important for communicating with hippocampal neurons. As a result, learning and memory are compromised.

Figure 2. Diagram comparing NGF (in red) transport in healthy neurons (panel a) and neurons, in which NGF transport is not working properly (panel b). In b), NGF is unable to travel to the cell nucleus. This causes the BFCN to shrink.

Evidence in Down syndrome, AD, and other neurodegenerative diseases, suggests that shrinkage and loss of BFCNs may contribute to cognitive decline (5-7) and that NGF plays a role in the degeneration of these BFCNs (8). Research has also suggested that the amount of NGF transported to the BFCNs is decreased in Down syndrome and AD (See reference 9 for a review).

Figure 3. Comparison of human chromosome 21 with corresponding chromosomes of Down syndrome mouse models Ts65Dn and Ts1Cje. Note, that the Ts1Cje mouse does not contain an extra copy of the App gene.

Based on these earlier findings, Salehi and colleagues focused their research on defining the genes that cause decreased transport of NGF, and how this might contribute to the degeneration of BFCNs. For their experiments, Salehi et al. (2006) took advantage of two well-studied mouse models of Down syndrome: Ts65Dn and Ts1Cje (For a review of these mice see News & Views No. 2). Both models have an extra chromosome containing a subset of genes found on human chromosome 21 (See Figure 3). The difference between the two mouse models is that the Ts65Dn mouse contains an extra copy of approximately 140 genes found on human chromosome 21, whereas the Ts1Cje mouse contains about 100 extra genes. Salehi et al. conducted various experiments in which they compared NGF transport and BFCNs in Ts65Dn mice with Ts1Cje and normal mice.

They found that transport of NGF was significantly reduced in the BFCNs of the Ts65Dn mice compared to normal control mice. Interestingly, NGF transport was less severely reduced in the Ts1Cje mice. In addition, they found an increased amount of NGF in the hippocampus of Ts65Dn mice, compared with control and Ts1Cje mice. Since the hippocampus is the site of NGF production, this finding suggested that enough NGF is being produced in the Ts65Dn mice, but that it somehow doesn’t reach its target, the nucleus of the BFCNs.

Next, the scientists analyzed the number and size of BFCNs in elderly Ts65Dn, Ts1Cje and control mice, to see if there were any differences that could be attributed to decreased NGF transport. They found that there was indeed a significant decrease in the size as well as number of BFCNs in the Ts65Dn mice. In contrast, the number of BFCNs in the Ts1Cje mice did not differ significantly from normal mice and the cells were not as small as in Ts65Dn.

What could possibly lead to such significantly different results in the two mouse models?
Recall that the Ts65Dn mouse contains about 40 more genes than Ts1Cje. One or several of those 40 genes present in the Ts65Dn mouse, but not in Ts1Cje, must be responsible for the observed effects. Because of its key role in AD, the amyloid precursor protein (App) gene revealed itself as a plausible candidate. The Ts65Dn mouse has three copies of this gene, whereas the Ts1Cje mouse only has two copies (See Figure 3). Using a genetic approach, Salehi et al. (2006) showed that increased App gene dose and overexpression indeed contribute to disrupted transport of NGF and thereby to the degeneration of BFCNs in Ts65Dn mice.

What are the implications of these findings for people with Down syndrome?

Salehi et al. have shown that a specific gene called App can be linked to the degeneration of BFGNs in a mouse model of Down syndrome. Since this gene is also associated with AD, these findings support the hypothesis that neurodegeneration and cognitive decline in older people with Down syndrome are associated with the chromosome 21 region that contains the APP gene.

The importance of the role of the APP gene in Down syndrome is further supported by two other reports. In one report (10), a woman with Down syndrome died at age 78 without any signs of dementia. At autopsy, her brain revealed no AD pathology. This is quite remarkable, since virtually all people with Down syndrome show AD pathology when they are about 40 years old. It turned out that this person only had two copies of the APP gene instead of the expected three. In a second report (11), a research team analyzed five families in which multiple members showed early onset AD with abnormal brain vasculature. Interestingly, all affected family members had a short extra segment of chromosome 21 that included the APP gene. These authors conclude that the APP gene and perhaps some of its surrounding genes, when triplicated, cause early onset familial AD.

The findings by Salehi and colleagues are very exciting for several reasons.

In more general terms, they provide additional evidence that in a mouse model, a complex disorder such as Down syndrome can be broken down into different constituents and that each sign or symptom can be related to the overexpression of a specific gene or a small group of genes. These results also confirm that using mouse models is a good approach to understanding gene dosage effects in Down syndrome and other disorders.

More specifically, the findings by Salehi et al. provide a target gene that might have therapeutic potential for preventing or delaying cognitive decline in Down syndrome. If an overexpression of the App gene can lead to such drastic changes in the brain, then therapy that reduces this overexpression should be very effective. Experiments by Cooper et al. (2001) have already demonstrated that, by injecting NGF into the brains of Ts65Dn mice, the BFCN degeneration could be recovered. Obviously, this is a very invasive method that cannot be applied to humans at this point. However, perhaps reversal of failed NGF transport could be achieved by targeting the App gene or protein. Even a small decrease in App expression might potentially prevent or at least delay the onset of cognitive decline in people with Down syndrome, by keeping NGF transport intact and BFCNs healthy.

Lastly, overexpression of the APP gene is implicated in the neuropathology of AD as well as Down syndrome. Therefore, therapeutic strategies for AD, which target APP could potentially be useful in preventing or delaying cognitive decline in people with Down syndrome.

In summary, Dr. Salehi and his colleagues have shown that an extra copy of a gene called App causes degeneration of BFCNs in a mouse model of Down syndrome. Since shrinkage and loss of BFCNs may contribute to cognitive decline in Down syndrome, it is very exciting to have found a specific gene that is linked to this degeneration. The APP gene has great therapeutic potential for the prevention or delay of cognitive decline in people with Down syndrome.


References

Wisniewski, KE, Dalton, AJ, McLachlan, C, Wen, GY, and Wisniewski, HM (1985) Alzheimer’s disease in Down’s syndrome: clinicopathologic studies. Neurology. 35:957-961.

Lai, F and Williams, RS (1989) A prospective study of Alzheimer’s disease in Down syndrome. Arch Neurol. 46:849-853.

Hattori, M et al. (2000) The DNA sequence of chromosome 21. Nature. 407(6784):283-284.

Sofroniew, MV, Howe, CL, and Mobley, WC (2001) Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci. 24:1217-1281.

Mann, DM, Yates, PO, Marcyniuk, B, and Ravindra, CR (1985) Pathological evidence for neurotransmitter deficits in Down’s syndrome of middle age. J Ment Defic Res. 29(Pt. 2):125-135.

Whitehouse, PJ, Price, DL, Clark, AW, Coyle, JT, and DeLong, MR (1981) Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol. 10:122-126.

Salehi, A, Lucassen, PJ, Pool, CW, Gonatas, NK, Ravid, R, and Swaab, DF (1994) Decreased neuronal activity in the nucleus basalis of Meynert in Alzheimer’s disease as suggested by the size of the Golgi apparatus. Neuroscience. 59:871-880.

Cooper, JD, Salehi, A, Delcroix, JD, Howe, CL, Belichenko, PV, Chua-Couzens, J, Kilbridge, JF, Carlson, EJ, Epstein, CJ, and Mobley, WC (2001) Failed retrograde transport of NGF in a mouse model of Down’s syndrome: reversal of cholinergic neurodegenerative phenotypes following NGF infusion. Proc Natl Acad Sci. 98:10439-10444.

Salehi, A, Delcroix, JD, and Mobley, WC (2003) Traffic at the intersection of neurotrophic factor signaling and neurodegeneration. Trends Neurosci. 26, 73-80.

Prasher, VP, Farrer, MJ, Kessling, AM, Fisher, EMC, West, RJ, Barber, PC, Path, MRC, and Butler, AC (1998) Molecular mapping of Alzheimer-type dementia in Down’s syndrome. Ann Neurol. 43:380-383.

Rovelet-Lecrux, A, Hannequin, D, Raux, G, Le Meur, N, Laquerrière, A, Vital, A, Dumanchin, C, Feuillette, S, Brice, A, Vercelletto, M, Dubas, F, Frebourg, T, and Campion,D (2006) APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nature Genetics. 38(1):24-26.