A paper in this week’s PNAS online suggests that one amyloid is pretty much like another in the havoc it can wreak on the brain. Researchers in the laboratory of Mathias Jucker, at the University of Tübingen in Germany, report that the amyloidogenic ADan peptide, in their mouse model of familial Danish dementia, acts a lot like Aβ does in mouse models of Alzheimer disease. In particular, ADan exacerbates tau pathology. Their work, the authors suggest, supports the hypothesis that amyloid-forming peptides are the source of neurodegeneration in Alzheimer’s as well as familial dementias.

Familial Danish dementia (FDD) and the related familial British dementia (FBD) are rare disorders, with only a few known affected families. “The Danish and the British dementias have neurofibrillary tangles, as in Alzheimer disease, but the amyloid is not Aβ,” said co-author Jorge Ghiso of the New York University School of Medicine in Manhattan. “Yet with this other amyloid, you can produce the same pathology,” he said, referring to the effects on tau. The implication for Alzheimer’s researchers, Jucker proposed, is that scientists can now test hypotheses about amyloid in the ADan model mice, allowing them to tease apart the effects of Aβ from the effects of amyloids in general. First author Janaky Coomaraswamy, at the University of Tübingen, led the project.

FDD causes progressive dementia as well as visual and auditory problems. Both FDD and FBD are caused by mutations that eliminate a stop codon in the BRI2 gene, lengthening the carboxyl-terminal tail of the encoded protein by 11 amino acids (see ARF related news story on Vidal et al., 1999). A furin-like protease cleaves BRI2, releasing the tail, which is amyloidogenic in its longer incarnation. The process is reminiscent of APP processing, which, of course, yields the amyloidogenic Aβ that is linked to Alzheimer disease. Some work even suggests that BRI2 and APP interact, with wild-type BRI2 diminishing Aβ production (see ARF related news story on Matsuda et al., 2005; Matsuda et al., 2008; Kim et al., 2008).

Jucker and colleagues engineered mice to express the human, FDD-associated BRI2 gene under control of the PrP prion promoter, and examined eight mice at two, four, 10, and 18 months of age. The mice evinced age-dependent accumulation of the ADan peptide starting as young as two months old. By the time the mice reached 18 months, the researchers observed ADan plaques throughout the brain. ADan plaques, which commonly formed in the blood vessels of the brain—like some Aβ deposits do—stained positive for Congo red, a marker of amyloid structures. These mice also took longer than control animals to find the safe platform in the Morris water maze test of spatial learning. They also failed to gain weight normally, and were sacrificed by two years of age because they were simply too lean to survive. Jucker’s ADan mice are similar to another ADan transgenic model published last year (see ARF related news story on Vidal et al., 2008). A knock-in mouse, in contrast, showed no evidence of abnormal amyloid deposition (Giliberto et al., 2009).

One important question in the Alzheimer’s field, Jucker said, is how Aβ oligomers and plaques relate to tau aggregates and neurofibrillary tangles, and which of the structures forms first. The study authors knew that crossing AD model mice (carrying mutant human presenilin-1 and APP) with mice expressing mutant human tau[P301S] results in more tau tangles than the tau P301S mutation alone. They wondered if ADan would have the same effect, and crossed their ADan mice with tau[P301S] mice to find out. Coomaraswamy and colleagues stained brain sections from the resulting double-transgenic mice with Gallyas silver stain, which binds tau lesions. The ADan/tau double-transgenics had 50 times more Gallyas-stained cells than single-transgenic tauP301S mice.

The researchers also stained brain sections with the AT8 antibody that labels inclusions containing phosphorylated tau, a harbinger of neurofibrillary tangles. The double--transgenic mice had 18-fold more phospho-tau lesions than tau[P301S] single-transgenic littermates. These conclusions were based on six or seven animals per genotype.

Coomaraswamy and colleagues suggest, based on their data, that both Aβ and ADan have the same effect on tau inclusion formation. “What is common between the two things? It’s the amyloid structure,” Jucker said. “That is apparently what triggers the tau pathology.”

Some researchers question the importance of Aβ in AD pathogenesis, but this paper provides some support for the amyloid hypothesis, said Todd Golde of the University of Florida in Gainesville, who was not involved in the study. “We should not dismiss the formation of amyloid as being pathogenic,” he said. He thought the FDD mouse model, with amyloidogenic peptides leading to pathology, mimics human disease well; however, he noted the tau formations in the ADan/tau[P301S] mice do not look quite like classical tangles to his eye.

Mouse models of FDD will be useful in testing therapeutics for the disease, but will also be useful for Alzheimer’s studies, Jucker contends. He intends to repeat classic experiments done in Aβ mice to see if ADan has similar effects. For example, vaccinating AD model mice against Aβ causes side effects such as meningoencephalitis and edema. “Do you see the side effects when you vaccinate the Danish mouse [against ADan]?” he asked. If not, such a vaccine would be an appealing therapy for people with FDD; if so, it would shore up Jucker’s hypothesis that all amyloids behave the same, and allow researchers to look for a generic mechanism that leads to these side effects. Similarly, he is interested in performing electrophysiology with the new model. APP mice have seizures, he noted. “Is it the amyloid which induces these epileptic seizures, and is it specific for Aβ?” These further experiments will help determine how closely ADan mimics Aβ.—Amber Dance


  1. It is now possible, using sophisticated molecular engineering, to support all types of hypotheses, both ways. The truth is in therapeutical trials.

    View all comments by Andre Delacourte

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News Citations

  1. For Lack of a Stop Codon
  2. BRIdging Alzheimer Disease and British/Danish Dementias
  3. Bri2 Peptide Blocks Aβ Deposition in Mice

Paper Citations

  1. . A stop-codon mutation in the BRI gene associated with familial British dementia. Nature. 1999 Jun 24;399(6738):776-81. PubMed.
  2. . The familial dementia BRI2 gene binds the Alzheimer gene amyloid-beta precursor protein and inhibits amyloid-beta production. J Biol Chem. 2005 Aug 12;280(32):28912-6. PubMed.
  3. . BRI2 inhibits amyloid beta-peptide precursor protein processing by interfering with the docking of secretases to the substrate. J Neurosci. 2008 Aug 27;28(35):8668-76. PubMed.
  4. . BRI2 (ITM2b) inhibits Abeta deposition in vivo. J Neurosci. 2008 Jun 4;28(23):6030-6. PubMed.
  5. . Cerebral amyloid angiopathy and parenchymal amyloid deposition in transgenic mice expressing the Danish mutant form of human BRI2. Brain Pathol. 2009 Jan;19(1):58-68. PubMed.
  6. . Generation and initial characterization of FDD knock in mice. PLoS One. 2009;4(11):e7900. PubMed.

Further Reading


  1. . Modeling familial British and Danish dementia. Brain Struct Funct. 2010 Mar;214(2-3):235-44. PubMed.
  2. . Generating differentially targeted amyloid-beta specific intrabodies as a passive vaccination strategy for Alzheimer's disease. Mol Ther. 2009 Dec;17(12):2031-40. PubMed.
  3. . Maturation of BRI2 generates a specific inhibitor that reduces APP processing at the plasma membrane and in endocytic vesicles. Neurobiol Aging. 2011 Aug;32(8):1400-8. PubMed.
  4. . Genetics and molecular pathogenesis of sporadic and hereditary cerebral amyloid angiopathies. Acta Neuropathol. 2009 Jul;118(1):115-30. PubMed.
  5. . BRI2 as a central protein involved in neurodegeneration. Biotechnol J. 2008 Dec;3(12):1548-54. PubMed.

Primary Papers

  1. . Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease. Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7969-74. PubMed.