Conventional wisdom says that Down syndrome (DS) goes hand-in-hand with intellectual disability—but what if that was not true? Two recent papers suggest that a treatment for the cognitive deficits of Down syndrome may be more than just a pipe dream. Both studies find that Aβ, a potentially toxic peptide that is a major contributor to Alzheimer disease (AD), not only plays a key role in Down syndrome, but does so quite early in the disease. In a paper published June 3 in PLoS One, scientists led by Paul Greengard of The Rockefeller University, New York, revealed they could reverse learning deficits in a Down syndrome mouse model by lowering the levels of soluble Aβ in the brains of young mice. In another paper, reported May 20 in the same journal, researchers led by Lee Goldstein of Boston University, Massachusetts, reported that the characteristic cataracts seen in Down syndrome are composed of Aβ aggregates, and these cataracts may be one of the earliest signs of Aβ accumulation in a person with DS. Together, these studies hold out promise that scientists might find early diagnosis and treatment options for the cognitive deficits of Down syndrome.

There is a growing recognition that Down syndrome and AD share some common ground. People who have DS are at increased risk of developing AD late in life, most likely due to triplication of AD-associated genes on chromosome 21, in particular APP, the precursor to Aβ. Few experiments, however, have looked at the effects of APP overexpression and Aβ accumulation in people with Down syndrome early in life.

To examine the effect of early interventions, first authors William Netzer and Craig Powell made use of Ts65Dn transgenic mice, considered the gold standard of Down syndrome models. These mice carry a trisomy that is analogous to DS trisomy, including a triple copy of the APP gene, and show cognitive deficits by two to three months of age. The authors reasoned that since the γ-secretase inhibitor DAPT, which reduces Aβ levels in the brain, rescues cognitive deficits in the Tg2576 AD mouse model (Comery et al., 2005), DAPT might also have an effect on Down syndrome mice.

The authors treated four-month-old Ts65Dn mice with DAPT. After four days, levels of Aβ in the cortex were reduced to about 65 percent of control, as measured by Western blot analysis. More intriguingly, DAPT treatment also rescued the cognitive deficits of the Down syndrome mice, as determined by testing spatial learning and memory in the Morris water maze.

The improved learning was most likely due to the reduction in soluble Aβ levels, Netzer said. He noted that in the Tg2576 AD mice, DAPT improved cognition in as little as three hours, which is the amount of time required to reduce soluble Aβ levels by half. Soluble Aβ oligomers are widely considered to be the most toxic species, and Netzer speculated that oligomers may be the culprit in the young DS mice, even though the researchers did not directly measure oligomer concentration. “When you reduce Aβ production, effectively you’re reducing the concentration of Aβ, and oligomerization is in part a concentration-dependent phenomenon,” he said.

The authors plan to investigate how soluble Aβ might decrease cognitive abilities in Down syndrome. Since Aβ reduces excitatory synaptic transmission in the brain by encouraging removal of NMDA and AMPA receptors from the synapse (see ARF related news story on Snyder et al., 2005 and ARF related news story on Hsieh et al., 2006), the authors will examine the concentration of glutamate receptors at synapses in DAPT-treated and -untreated Down syndrome mice, and look for correlations with cognitive deficits. They also want to examine other physical changes in the brain such as spine density, Netzer said.

The clinical implications of this finding are exciting, as they suggest that at least some cognitive deficits in children with Down syndrome might be reversible with treatment. Because DAPT has toxic effects when taken long-term, however, there is no immediate clinical application for these results. “My prediction,” Netzer said, “is that once a safe Aβ-lowering drug is developed [for AD], I think people will take that into the clinic for Down syndrome adults and children.” Other γ-secretase inhibitors are currently the subject of intense investigation and clinical trials in the scientific community (see ARF related news story and ARF news story).

This study is admirable for its combination of simplicity and significance, noted Huntington Potter of the University of South Florida, Tampa. He cautioned, however, that there are several possible explanations for the results other than simply concluding that Aβ is solely responsible for cognitive deficits. “To us, the most likely is that in mice, Aβ plays a critical role in microtubule function, and that too much (or maybe even too little) changes microtubule-dependent localization of key receptors,” Potter wrote in an e-mail. “Alternatively, the inhibitor DAPT may have more extensive beneficial effects than only reducing Aβ production.”

The paper by Goldstein and colleagues takes a different approach, examining the molecular composition of cataracts in the eyes of people with Down syndrome. Their results suggest the eye is not just the window to the soul, but a window to the brain.

Their research builds on their earlier work, showing that the unique cataracts that develop in people with late onset AD consist of aggregated Aβ deposits (Goldstein et al., 2003). These AD cataracts, called equatorial supranuclear cataracts, occur in a ring around the periphery of the eye, rather than in the center, and are unrelated to normal age-related cataracts.

Scientists have known for over a hundred years that distinctive cataracts also occur in the eyes of people with Down syndrome, but the composition and cause of these cataracts have been a mystery. First authors Juliet Moncaster, Roberto Pineda, and Robert Moir examined postmortem lens specimens under a microscope to confirm that DS cataracts had the same physical properties and appearance as late-stage AD cataracts. The authors then demonstrated that these cataracts contained Aβ peptides by staining with Congo red and anti-Aβ antibodies. They used mass spectrometry to directly confirm the presence of Aβ peptide in lens extracts. Finally, they showed in vitro that soluble Aβ induces the major protein of the lens, αB-crystallin, to form aggregates consistent with those seen in Down syndrome cataracts. All of their results indicate that DS cataracts are indistinguishable from the cataracts seen in late onset AD.


Stereo image pair demonstrating mature supranuclear pathology in the lens of a 64-year-old male subject with Down syndrome. The distinctive equatorial supranuclear cataract in this lens exhibits a characteristic circumferential phenotype often observed in mature adults with Down syndrome. In this lens, the Down syndrome cataract is evident as a circumferential annular halftoroid band of opacification in the deep cortical and supranuclear subregions of the lens (shown with intact zonules). This dramatic Down syndrome cataract is identical to the subequatorial supranuclear cataracts observed in advanced Alzheimer disease (Goldstein et al., 2003). The cataracts associated with Down syndrome and Alzheimer disease are composed of cytosolic deposits of amyloid-β (Aβ), the same pathogenic peptide that age-dependently accumulates as neuritic plaques in the brain in both disorders. This supranuclear cataract phenotype is not observed in other ophthalmic or neurological diseases, nor in aged normal subjects (Moncaster et al., 2010). Image credit: Lee Goldstein and PLoS One

One of the noteworthy features of these DS cataracts is that the first molecular changes appear very early, before the age of two, or perhaps even earlier. This is long before Aβ accumulation becomes apparent in the brain, Goldstein said, which implies these cataracts could provide a very sensitive preview of processes occurring in the brain. Another intriguing finding is that, although Aβ accumulation increases with age, the rate of deposition varies greatly among individuals. Goldstein suggested that by correlating the rate of Aβ deposition in the eye with a person’s genotype, it might be possible to discover genes that modify Aβ expression, which could have implications beyond Down syndrome.

The potential for a clinical diagnostic tool is one of the most exciting aspects of this work. The authors developed a custom laser-based eye scanner, Goldstein said, that can non-invasively detect the earliest eye changes in Down syndrome. Long before DS end-stage cataracts form, the eyes develop intracellular Aβ deposits in the fiber cells of the lens. These deposits are smaller than the wavelength of light, and so scatter light in a characteristic fashion that can be used to diagnose their presence.

The next step in this research would be to conduct clinical trials to validate the technique’s usefulness as an early diagnostic, Goldstein said, a possibility he is actively investigating. He said that people with Down syndrome who have accelerated Aβ deposition are most likely to benefit from any new therapies that might become available. “There’s reason to be optimistic that we can halt or at least slow the progression of the AD component of the disorder,” Goldstein said. He is also hopeful that in the future, eye scans might be useful for therapeutic monitoring, as a non-invasive way to track whether a treatment is successfully reducing Aβ levels in the brain.

The work reported in these two papers is complementary, Goldstein added, because diagnosis and treatment are flip sides of the same coin. To intervene in a disease such as Down syndrome, you need both an early detection method and an effective treatment. There are more indications than ever before that a day is coming when we could have both.—Madolyn Bowman Rogers


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Comments on News and Primary Papers

  1. Some papers are especially admirable for their combination of simplicity and significance. Such is the case of the recent report by Netzer and colleagues who show that a γ-secretase inhibitor restores cognitive function in a mouse model of Down syndrome. All trisomy 21/DS individuals develop AD pathology by age 30-40 and usually exhibit AD-like cognitive deficits by age 50. We and others have also shown that all AD individuals harbor trisomy 21 cells in their brains and other tissues and, most recently, that Aβ can induce microtubule defects leading to chromosome mis-segregation and aneuploidy including trisomy 21 (Granic et al., 2009). Thus, AD and DS are intimately linked at many levels.

    Because the APP gene resides on chromosome 21, it has been assumed that the extra copy of chromosome 21 in DS underlies the development of AD in these individuals. This inference was strongly supported by the finding of families with inherited, early-onset Alzheimer disease caused by the mere duplication of the APP gene region on one chromosome 21 (Sleegers et al., 2006; Rovelet-Lecrux, 2006). However, which parts of chromosome 21 are responsible for the developmental, including cognitive, alterations observed in young DS individuals is unknown and the subject of much research. Many genes, including S100β, APP, Ncam2, and Dyrk1a, have both logical and experimental arguments in favor of their involvement in the cognitive deficits in DS (for discussion, see Belichenko et al., 2007). However, further defining the Down syndrome critical region (DSCR) or the mental retardation (MR) critical region has been difficult. Work with DS patients with partial trisomy 21 due to chromosome translocation has suggested that there is no single DSCR responsible for all of the features of DS or even one region responsible for MR (Korenberg et al., 2004; Belichenko et al., 2007). One approach to investigating the genetic causes of DS is to develop mice that by virtue of either a translocation or Cre-lox directed recombination and deletion carry three, or zero copies of parts of mouse chromosome 16. For example, the mouse that Netzer and colleagues used, Ts65Dn, is the classic mouse trisomy 16 model of DS which carries three copies of 13Mb (~33 genes) at the end of mouse chromosome 16, corresponding to much of human chromosome 21. Although this mouse recapitulates many of the physical and cognitive features of DS, whether the whole region or smaller parts of it are necessary or sufficient is still debated. One group created transgenic mice with a smaller cohort of triplicated genes than in Ts65Dn and found that triplicating this region was not sufficient to cause cognitive deficits including hippocampal deficits shown by the Morris water maze, but that making that particular region disomic in a Ts65Dn background restored hippocampal learning to normal, indicating that it was necessary for this behavior (Olson et al., 2007). In contrast, another group using different mice and somewhat different tasks showed that a similar region of chromosome 16 was sufficient to confer cognitive deficits (Belichenko et al., 2009).

    These studies make it both exciting and surprising that Netzer and colleagues found that suppressing the product (Aβ) of one gene (APP) in the DSCR by a γ-secretase inhibitor is sufficient to restore cognitive function in the Ts65Dn mouse model of AD. There are several possible explanations for this finding beyond the simple conclusion that Aβ is solely responsible for the MR of DS. To us, the most likely is that in mice, Aβ plays a critical role in microtubule function, and that too much (or maybe even too little) changes MT-dependent localization of key receptors (see, e.g., Abisambra et al., 2010). Alternatively, the inhibitor DAPT may have more extensive beneficial effects than only reducing Aβ production. Finally, the mouse models of neurological disease may be inherently easier to “cure” with pharmacological interventions than would be expected from the genetics underlying the human or the mouse phenotype. This latter possibility is most concerning because it might also explain why so many drugs that are effective in mouse models of AD turn out to be less or not effective in human trials. We may be facing a need to develop more robust assays of mouse behavior that cannot be modified by small changes in synaptic strength.


    . LDLR expression and localization are altered in mouse and human cell culture models of Alzheimer's disease. PLoS One. 2010;5(1):e8556. PubMed.

    . The "Down syndrome critical region" is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of Down syndrome. J Neurosci. 2009 May 6;29(18):5938-48. PubMed.

    . Alzheimer Abeta peptide induces chromosome mis-segregation and aneuploidy, including trisomy 21: requirement for tau and APP. Mol Biol Cell. 2010 Feb 15;21(4):511-20. PubMed.

    . Down syndrome phenotypes: the consequences of chromosomal imbalance. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4997-5001. PubMed.

    . Trisomy for the Down syndrome 'critical region' is necessary but not sufficient for brain phenotypes of trisomic mice. Hum Mol Genet. 2007 Apr 1;16(7):774-82. PubMed.

    View all comments by Huntington Potter
  2. There is a great need to develop a simple, non-invasive diagnostic test for Alzheimer disease. Many people, ourselves included, have tried to apply the old adage "The eyes…are the wyndowes of the mynde..." (T.Phaer; 1545 paraphrasing of Cicero) to the study of neurodegenerative disease. The paper by Moncaster and colleagues continues in this vein by assessing Alzheimer disease-linked pathology in the lenses of Down syndrome subjects’ eyes. Previous work by the same group (Goldstein et al., 2003) had shown amyloid deposits in lenses of AD subjects just as earlier studies had shown similar pathology in the retinas of AD subjects and mouse models of AD (e.g., Loffler et al, 1995; Frederise and Ren, 2002). Because trisomy 21/Down syndrome is easily identified, relatively common (~one in 750 live births), and inevitably leads to AD brain pathology by age 30-40, DS patients provide a special human population in which to study the earliest features of AD with the hope of gaining insight into the pathogenic pathway to the disease and of developing early diagnostics. In the current paper, Moncaster and his associate used Congo red birefringence, immunocytochemistry, and mass spectrometry peptide sequencing to demonstrate unequivocally that the Alzheimer Aβ peptide deposits early on (by age 22, and, at least by Western, by age two) in the lenses of DS patients in a manner essentially identical to the pathology observed in aged AD patients. Furthermore, in vitro experiments indicated that addition of Aβ to solubilized lens extracts increased protein aggregation as assayed by quasi-elastic light scattering. This result is interesting in light of previous work showing a direct interaction between αB-crystalin and Aβ that promotes Aβ neurotoxicity (Stege et al., 1999). Although the level of Aβ peptide in the lens is some fivefold less than in the DS or AD brain, the fact that an easily administered eye test for Alzheimer disease may come out of this work makes this paper particularly significant.


    . Lens defects and age-related fiber cell degeneration in a mouse model of increased AbetaPP gene dosage in Down syndrome. Am J Pathol. 2002 Dec;161(6):1985-90. PubMed.

    . Cytosolic beta-amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer's disease. Lancet. 2003 Apr 12;361(9365):1258-65. PubMed.

    . Immunoreactivity against tau, amyloid precursor protein, and beta-amyloid in the human retina. Invest Ophthalmol Vis Sci. 1995 Jan;36(1):24-31. PubMed.

    . The molecular chaperone alphaB-crystallin enhances amyloid beta neurotoxicity. Biochem Biophys Res Commun. 1999 Aug 19;262(1):152-6. PubMed.

    View all comments by Huntington Potter


News Citations

  1. Amyloid-β Zaps Synapses by Downregulating Glutamate Receptors
  2. AMPA Receptors: Going, Going, Gone in Aβ-exposed Synapses, PSD95 Knockouts
  3. Raising Our...Hoops?—No Rebounds With γ-Secretase Inhibitors
  4. DC: New γ Secretase Inhibitors Hit APP, Spare Notch

Paper Citations

  1. . Acute gamma-secretase inhibition improves contextual fear conditioning in the Tg2576 mouse model of Alzheimer's disease. J Neurosci. 2005 Sep 28;25(39):8898-902. PubMed.
  2. . Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci. 2005 Aug;8(8):1051-8. PubMed.
  3. . AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron. 2006 Dec 7;52(5):831-43. PubMed.
  4. . Cytosolic beta-amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer's disease. Lancet. 2003 Apr 12;361(9365):1258-65. PubMed.
  5. . Alzheimer's disease amyloid-beta links lens and brain pathology in Down syndrome. PLoS One. 2010;5(5):e10659. PubMed.

Further Reading

Primary Papers

  1. . Alzheimer's disease amyloid-beta links lens and brain pathology in Down syndrome. PLoS One. 2010;5(5):e10659. PubMed.
  2. . Lowering beta-amyloid levels rescues learning and memory in a Down syndrome mouse model. PLoS One. 2010;5(6):e10943. PubMed.