Degu Debut—The New Face of Sporadic Alzheimer’s Research?

Meet the degu. Native to Chile, these highly social rodents develop pathological hallmarks of Alzheimer’s disease, including Aβ and tau deposits. Cognition also declines as these animals age, according to a report in the August 6 Proceedings of the National Academy of Sciences online. “We believe these animals could present an attractive model for studying sporadic Alzheimer’s disease,” Alfredo Kirkwood, a senior author on the study, told Alzforum. Kirkwood, from Johns Hopkins University, Baltimore, Maryland, collaborated with researchers led by Adrian Palacios, Universidad de Valparaíso, Chile, to characterize pathology in these guinea pig relatives.

 

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Transgenic mice are the model of choice for studying AD the world over, but, as Kirkwood pointed out, they more accurately model early onset familial AD rather than the late-onset form of the disease. “If you want to study sporadic AD or evaluate a therapy, you would want to use a natural model,” said Kirkwood. “Right now there is no other reasonable model than the degu,” he suggested. Other animals that naturally develop AD-like pathology include lemurs (Bons et al., 1994; Delacourte et al., 1995) and Caribbean vervets (Lemere et al., 2004).

In 2005, researchers in Chile reported that degus, whose APP gene shares 97.5 percent homology with the human form, develop amyloid plaques and tau deposits (Inestrosa et al., 2005). Palacios and colleagues decided to look more closely at these animals, examining pathology, electrophysiology, and behavior at different ages. First author Alvaro Ardiles and coworkers found that, beginning at about three years old, degus show signs of cognitive decline. They perform poorly compared to younger animals in tests of learning and memory, and electrophysiological measurements reveal weak synaptic transmission and plasticity. The synaptic deficits seem related to loss of key postsynaptic proteins, including PSD-95, and AMPA and NMDA receptor subunits.

Amyloid plaques began to appear in the degu cortex by 30 months, extending to the hippocampus by 60 months. While the researchers found soluble Aβ oligomers in both young and old degus, the levels rose as the animals aged. Between 12 and 36 months, the degu brain sprouted more Aβ hexamers and dodecamers than seen in young animals. Intriguingly, as soluble Aβ oligomers and phosphorylated tau accumulated in the animals, they began performing poorly in learning and memory tasks. Soluble Aβ and tau also correlated with synaptic losses.

Degus cannot match the rapid development of pathology seen in some transgenic mouse models of AD. That might make researchers think twice about using them for routine drug testing, for example. “It is true that you may have to wait longer to see any effects, but the advantage is you have a natural progression,” said Kirkwood. The researchers plan to test several interventions in their animal colony, including levetiracetam, an anti-epileptic drug that calms hyperactive neural networks in humans and reverses behavioral deficits—including memory loss—in AD mouse models (see ARF related news story).—Tom Fagan

Comments

  1. A most interesting model for AD, but why specifically for the "sporadic" form? Chilean degus manifest "AD" beginning at about three years of age, whereas their "relatives," the Chilean guinea pigs, do not; Calabrian carriers of M146L in PS1 manifest AD at about 45 years of age, whereas their non-carrier relatives do not. The difference between Chilean degus and guinea pigs is, by definition, genetic, the same as the difference between Calabrian people. In the absence of demonstrated environmental causes, the null hypothesis is that late-onset "sporadic," i.e., apparently non-familial, human AD, is genetic with a large stochastic dispersion of the age at onset, as we observed for familial early onset AD. The absence of apparent familiality in late-onset AD is due to "statistical censorship," the theoretical, genetically determined, median age at onset of AD being older than the mean age of death from other causes (1).

    References:

    Bruni AC, Montesi MP, Salmon D, Gei G, Perre J, el Hachimi KH, Foncin JF. Alzheimer's disease: a model from the quantitative study of a large kindred. J Geriatr Psychiatry Neurol. 1992 Jul-Sep;5(3):126-31. PubMed.

    View all comments by Jean-François Foncin

  2. A most interesting animal model of AD, not only with the Aβ peptide, intracellular and extracellular accumulations of tau protein, and ubiquitin, but also demonstrating strong astrocytic responses and acetylcholinesterase (AChE)-rich pyramidal neurons (Inestrosa et al., 2005). Analysis of different regions from the cerebral cortex (frontal, parietal, temporal, and entorhinal) and hippocampus of young and aged wild-type degus with anti-human Aβ peptide (1-40) antibodies found prominent Aβ deposited in both cerebral cortex and hippocampus of the aged degus (Hardy and Higgins 1992).

    Increased GFAP-positive astrocytes have also been seen in the aged degu brain, as well as in the human brain, with age, and in older rats. This phenomenon does not appear to reflect astrocyte gliosis that occurs in association with neurofibrillary tangles and senile plaques, but rather as an astrocyte reaction in the whole brain related to an accumulation of GFAP (Nichols et al., 1993).

    Ardiles and associates in Chile found that during aging, degus display a significant reduction in synaptic memory; object recognition memory, tested using an alternance T-maze task; and object recognition in an open-field arena (Ardiles et al., 2011).

    We can only hope that Dr. Kirkwood’s Octodon degus colony will be large enough to allow other Alzheimer’s disease researchers here in the United States to conduct research with this animal model of AD.

    See also:

    Ardiles A, et al., β-Amyloid dodecamers and hyperphosphorylated Tau correlates with synaptic and cognitive impairments in aged Octodon degus. 2011. Paper presented at Reunion Annual Sociedad Chilena de Neuroscienca, Las Cruces, Chile.

    References:

    Inestrosa NC, Reyes AE, Chacón MA, Cerpa W, Villalón A, Montiel J, Merabachvili G, Aldunate R, Bozinovic F, Aboitiz F. Human-like rodent amyloid-beta-peptide determines Alzheimer pathology in aged wild-type Octodon degu. Neurobiol Aging. 2005 Jul;26(7):1023-8. PubMed.

    Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science. 1992 Apr 10;256(5054):184-5. PubMed.

    Nichols NR, Day JR, Laping NJ, Johnson SA, Finch CE. GFAP mRNA increases with age in rat and human brain. Neurobiol Aging. 1993 Sep-Oct;14(5):421-9. PubMed.

    View all comments by Trent Nichols

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References

News Citations

  1. Anticonvulsants Reverse AD-like Symptoms in Transgenic Mice

Paper Citations

  1. Bons N, Mestre N, Ritchie K, Petter A, Podlisny M, Selkoe D. Identification of amyloid beta protein in the brain of the small, short-lived lemurian primate Microcebus murinus. Neurobiol Aging. 1994 Mar-Apr;15(2):215-20. PubMed.
  2. Delacourte A, Sautière PE, Wattez A, Mourton-Gilles C, Petter A, Bons N. Biochemical characterization of Tau proteins during cerebral aging of the lemurian primate Microcebus murinus. C R Acad Sci III. 1995 Jan;318(1):85-9. PubMed.
  3. Lemere CA, Beierschmitt A, Iglesias M, Spooner ET, Bloom JK, Leverone JF, Zheng JB, Seabrook TJ, Louard D, Li D, Selkoe DJ, Palmour RM, Ervin FR. Alzheimer's disease abeta vaccine reduces central nervous system abeta levels in a non-human primate, the Caribbean vervet. Am J Pathol. 2004 Jul;165(1):283-97. PubMed.
  4. Inestrosa NC, Reyes AE, Chacón MA, Cerpa W, Villalón A, Montiel J, Merabachvili G, Aldunate R, Bozinovic F, Aboitiz F. Human-like rodent amyloid-beta-peptide determines Alzheimer pathology in aged wild-type Octodon degu. Neurobiol Aging. 2005 Jul;26(7):1023-8. PubMed.

Other Citations

Further Reading

Primary Papers

  1. Ardiles AO, Tapia-Rojas CC, Mandal M, Alexandre F, Kirkwood A, Inestrosa NC, Palacios AG. Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2012 Aug 21;109(34):13835-40. PubMed.

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