- Open Access
Revisiting rodent models: Octodon degus as Alzheimer’s disease model?
© The Author(s). 2016
- Received: 11 August 2016
- Accepted: 11 August 2016
- Published: 26 August 2016
Alzheimer’s disease primarily occurs as sporadic disease and is accompanied with vast socio-economic problems. The mandatory basic research relies on robust and reliable disease models to overcome increasing incidence and emerging social challenges. Rodent models are most efficient, versatile, and predominantly used in research. However, only highly artificial and mostly genetically modified models are available. As these ‘engineered’ models reproduce only isolated features, researchers demand more suitable models of sporadic neurodegenerative diseases. One very promising animal model was the South American rodent Octodon degus, which was repeatedly described as natural ‘sporadic Alzheimer’s disease model’ with ‘Alzheimer’s disease-like neuropathology’. To unveil advantages over the ‘artificial’ mouse models, we re-evaluated the age-dependent, neurohistological changes in young and aged Octodon degus (1 to 5-years-old) bred in a wild-type colony in Germany. In our hands, extensive neuropathological analyses of young and aged animals revealed normal age-related cortical changes without obvious signs for extensive degeneration as seen in patients with dementia. Neither significant neuronal loss nor enhanced microglial activation were observed in aged animals. Silver impregnation methods, conventional, and immunohistological stains as well as biochemical fractionations revealed neither amyloid accumulation nor tangle formation. Phosphoepitope-specific antibodies against tau species displayed similar intraneuronal reactivity in both, young and aged Octodon degus.
In contrast to previous results, our study suggests that Octodon degus born and bred in captivity do not inevitably develop cortical amyloidosis, tangle formation or neuronal loss as seen in Alzheimer’s disease patients or transgenic disease models.
- Neurodegenerative diseases
- Amyloid beta-Peptides
- Tau proteins
- Alzheimer’s disease
- Animal models
- Octodon degus
Senile plaques, a hallmark of Alzheimer’s disease (AD), were long suggested to initiate the destructive cascade to progressive neuronal dysfunction and death. Nowadays small, soluble oligomers of β-amyloid (Aβ) are deemed the primary toxic species . These oligomers disrupt a variety of receptors , increase membrane permeability  and are suspected to induce hyperphosphorylation and aggregation of tau . Physiologically, Aβ is largely eliminated from the brain by LRP1  and several ABC transporters (reviewed in [5, 6]). The vast majority of cases occur sporadically and a large series of risk factors have been identified, including age, type 2 diabetes, high blood pressure, and various genetic factors like specific alleles of apolipoprotein E (APOE) [7, 8].
A small proportion of AD cases involve genetic variations which entail alterations in amount, ratio or amino acid sequence of Aβ . However, these rare inherited forms are the fundament of both, disease models and our current understanding of AD. Due to a lack of alternatives, the main focus lies on the usage of these genetically manipulated research animals (thus non-sporadic AD models), which restricts the progress of research and limits the scope of detailed analyses. To successfully combat the sporadic form of AD, models that develop the disease on a more ‘natural’ basis would certainly help to understand the underlying mechanisms which are essential for developing advanced and efficient therapy options.
The aim of the present study was to critically re-evaluate the suitability of degus as ‘natural’ AD model. To characterize amyloidosis and tau deposition, different cortical and hippocampal regions of young (1-year-old) and aged (5-years-old) wild-type, colony-bred degus were screened for neurodegenerative changes.
Drugs and chemicals used in the study were purchased from Carl Roth, Karlsruhe, Germany; except for those specifically mentioned.
Wild-type degus used in the present study were bred at the Institute of Biology, Otto-von-Guericke-University Magdeburg. Degus were housed in a climate-controlled environment (22 °C, 55 ± 5 % humidity) on a 12 h light/dark cycle with an enriched environment. Social enrichment was provided by housing in same sex groups of up to 4 animals. Sensory, motor and cognitive enrichment was provided by housing the animals in large cages (510x420x680 mm3, EBECO, Castrop Rauxel, Germany), equipped with a drinking bottle, burrows for hiding, a running wheel (Europet-Bernina International, Iserlohn, Germany) for physical exercise and material for nest building. Nutritional enrichment was provided by providing dry bread, fresh vegetables and fresh tree branches in addition to the regular pellet food (rat diet pellets and cereals; ssniff Spezialdiäten, Soest, Germany) ad libitum. A first cohort of degus was immunohistochemically analysed (J.P.) in two groups: young (12 months) and aged (60 months), both sexes, at least two animals per sex and age group. A second cohort from the same colony was independently analysed in another neuropathological laboratory (C.K.) and used for quantitative and western blot analyses: seven animals (age in months: 3, 24, 25, 56, 56, 65, and 65)
Tg-mice, harbouring mutant human amyloid precursor protein (KM670/671NL) and presenilin 1 (L166P) both driven by murine Thy1.2-promotor , were kindly provided by the University of Tübingen, Germany. All mice were housed in a climate-controlled (22 °C) environment on a 12 h light/dark cycle in same sex groups of up to 4 animals and free access to food and water. All experiments were conducted in accordance to the EU and state law of Saxony-Anhalt and approved by the local animal ethics committee.
Sequences & alignments
Accession numbers of featured proteins from the NCBI Protein database (http://www.ncbi.nlm.nih.gov/protein/)
Amyloid-beta A4 protein isoform a precursor
Microtubule-associated protein tau
Animals were sacrificed by cervical dislocation and immediately perfused with 50 mL PBS followed by 50 mL PFA for fixation. Paraffin-embedded, 4 μm-thick coronal sections were deparaffinised and stained using Haematoxylin and Eosin. Immunohistochemical analyses were performed using Bond-Max™ (Leica Microsystems, Wetzlar, Germany) automated staining system as described previously [5, 26–28]. Epitope retrieval was carried out as follows: 5 min in 95 % (v/v) formic acid for 6F3D, 4G8 and 6E10; 20 min in EDTA buffer pH 9.0 for IBA1 and AT180; 10 min enzymatic digestion (Bond Enzyme Pretreatment Kit, Leica Biosystems Nussloch, Nussloch, Germany) for GFAP or 20 min in citric acid buffer pH 6.0 for NeuN, AT8 and AT100. Antibodies against ionized calcium-binding adapter molecule 1 (IBA1 1:1000, 019-19741, Wako Chemicals, Neuss, Germany), glial fibrillary acid protein (GFAP, 1:500, Z033401, Dako Deutschland, Hamburg, Germany), neuronal nuclear antigen (NeuN, 1:500, MAB377, Merck Chemicals, Darmstadt, Germany) phosphorylated tau (AT8, 1:50, MN1020; AT100, 1:500, MN1060; AT180, 1:50, MN1040, Thermo Fisher Scientific, Waltham, MA, USA); β-amyloid (6E10, 1:100, SIG-39320, Covance Research Products, Denver. PA, USA; 4G8, 1:2000, SIG-39220, Covance Research Products, Denver. PA, USA; 6F3D, 1:100, M0872, Dako Deutschland, Hamburg, Germany) were used according to manufactures instructions. Slides were developed using Bond™ Polymer Refine Detection kit (Leica Microsystems, Wetzlar, Germany). For Campbell-Switzer staining, paraffin-embedded, 4 μm-thick coronal sections were deparaffinised, stirred for 5 min in ammonium hydroxide and washed twice in distilled water for 1 min. Sections were incubated for 40 min in Silver-Pyridine-Carbonate solution (14 % (v/v) pyridine, 0.49 % (w/v) silver nitrate, 0.37 % (w/v) potassium carbonate) followed by 3 min in citric acid and washed in acetate buffer (33.6 mM sodium acetate, 14.4 mM acetic acid, pH 4.99). Sections were developed in developer solution (236 mM sodium carbonate, 12.5 mM ammonium nitrate, 5.9 mM silver nitrate, 1.7 mM tungstosilicic acid, 0.87 mM formaldehyde) under a light source for about 6 min. Sections were washed three times in acetate buffer and once in distilled water, each for 30 s. Sections were finally placed in 0.5 % (w/v) sodium thiosulfate solution for 45 s, washed twice in distilled water and subsequently mounted. Slides were digitized using MIRAX MIDI Scanner (Carl Zeiss MicroImaging, Jena, Germany). The scanned slides were processed using the free Pannoramic Viewer software (3DHISTECH, Budapest, Hungary), and analysed under blinded conditions using either AxioVision (Carl Zeiss Imaging Solutions; Munich, Germany) or ImageJ (Wayne Rasband, National Institutes of Health, Bathesda, MD, USA) and the ITCN plugin (Thomas Kuo and Jiyun Byun, University of California, CA, USA).
Four-step fractionation and quantification of Aβ
Animals were sacrificed by cervical dislocation and transcardially perfused with PBS. The brain was immediately snap-frozen in liquid nitrogen and stored at −80 °C. Fractionation of brain tissue was performed by preparative ultracentrifugation as described previously . In brief, brain tissue was homogenated in 9 volumes of TBS buffer (150 mM sodium chloride, 50 mM Tris, pH 7, supplemented with protease inhibitor, Complete EDTA-free, Roche, Basel, Switzerland) and subsequently centrifuged (100,000 g, 4 °C, 1 h). The supernatant (TBS-fraction, soluble Aβ) was harvested, pellet was sonicated in 100 μl TBS/ 1 % (v/v) Triton X-100 and centrifuged again (100,000 g, 4 °C, 1 h). The supernatant (TX-100-fraction, detergent soluble Aβ) was harvested, the pellet was sonicated in TBS/ 2 % (w/v) SDS and centrifuged (100,000 g, room temperature, 1 h). Supernatant (SDS-fraction, protein bound Aβ) was harvested and the remaining pellet was finally resolved in 70 % formic acid (FA-fraction, insoluble Aβ). For quantification, SDS-fraction was diluted 20-fold in TBS and FA-fraction was neutralized with 19 volumes of 1 M Tris (pH 11).
Quantification was performed using the Human/Rat β-amyloid (40) or (42) ELISA Kit (Wako Chemicals, Neuss, Germany) according to the manufacturer's instructions, which uses BNT77 (epitope: amino acids 11-16) and BA27 (Aβ40-specific) or BC05 (Aβ42-specific), respectively .
Brain tissue was mixed with 9 volumes of TBS buffer (supplemented with protease and phosphatase inhibitor, Sigma-Aldrich, St. Louis, MO, USA), homogenized (total fraction) and centrifuged (130,000 g, 4 °C, 20 min). The pellet was resuspended in RIPA buffer (150 mM sodium chloride, 50 mM Tris, 0.5 % (w/v) deoxycholic acid, 1 % (v/v) Triton X-100, 0.5 % (w/v) SDS, 25 mM EDTA, pH 8 supplemented with protease and phosphatase inhibitor) and centrifuged again (130,000 g, 4 °C, 20 min). Supernatant was discarded; pellet was resuspended in 70 % formic acid and centrifuged (130,000 g, 4 °C, 20 min). Supernatant (FA-fraction) was neutralized with two volumes of neutralization buffer (5 M sodium hydroxide, 0.5 M Tris, 0.25 M monosodium phosphate). Proteins were precipitated using 2,2,2-trichloroacetic acid (25 % (v/v) TCA) for 30 min at 4 °C and subsequently separated by centrifugation (22,000 g, 4 °C, 15 min). Resulting pellet (insoluble fraction) was washed two times with cold acetone and subsequently air-dried.
Total and insoluble fractions were separated on a reducing 4–12 % Bis-Tris gel (Thermo Fisher Scientific, Waltham, MA, USA) and subsequently transferred to nitrocellulose membrane. Phosphorylated tau was detected using AT8 (1:1,000, MN1020, Thermo Fisher Scientific, Waltham, MA, USA) and total tau levels using HT7 antibody (1:1,000, MN1000, Thermo Fisher Scientific, Waltham, MA, USA), and protein expression was normalized with internal control anti-actin (1:10,000, Sigma-Aldrich, St. Louis, MO, USA).
For all quantifications, animals of either sex were used (n ≥ 2 per sex; n ≥ 4 per group), statistical significance (p ≤ 0.05) was determined using unpaired t-tests with Welch’s correction (Prism 6, GraphPad Software La Jolla, CA, USA).
To evaluate the extent of any cortical amyloidosis and neuronal destruction, a modified Campbell-Switzer stain was applied, but no extracellular deposits were exposed (Fig. 2i, j). This result was supported by thioflavin T stains which revealed no specific cortical fluorescence as well (Fig. 2k, l).
Levels of insoluble Aβ in transgenic AD models and wild-type rodents
In the near future, aging societies will be particularly challenged by age-related diseases demanding intensive care. Exceptional research endeavours are necessary to face these approaching challenges. Thus, reliable and accurate animal models are one of the major prerequisites in basic research. Although transgenic rodent models of AD are constantly refined, no model yet mimics all pathological features of this complex disease. More accurate models maintaining the beneficial characteristics of rodents would lead to a better understanding and more expedient therapeutic approaches. Degus were described as a promising natural model of Alzheimer’s disease during the last years by a Chilean group. However, in our studies we were unable to detect any systematic occurrence of the typical histopathological hallmarks of AD in relation to age. Haematoxylin and Eosin as well as NeuN stains showed not more than slight differences between young and aged degus, rather indicative for the natural aging process than pathological neurodegeneration. In contrast to previous results from Inestrosa et al. , we could not detect elevated GFAP expression in old degus compared to young animals. The lack of signs for microglial and astrocytic inflammation further reiterates the absence of a pathological degeneration in the examined brains of the old degus.
The sparse intracellular reactivity of anti-Aβ clone 6E10, which was lacking in clone 4G8, clone 6F3D, Campbell-Switzer and thioflavin T stains, most likely indicates an unspecific reaction . In contrast, no sign of any extracellular deposition of Aβ was detected in aged animals by any of the applied staining methods (Fig. 3). Quantitative measurements underpinned the absence of considerable amounts of insoluble Aβ (Fig. 4) and revealed Aβ-levels that are in the same range as those in wild-type mice  and below those of wild-type naked mole rats .
Consistent with results of van Groen et al. no significant neuronal loss was found in the brain of 5-years-old degus . These findings are in sharp contrast to observations in brains of degus obtained from their natural habitat, in which prominent intra- and extracellular Aβ deposits in cortices and hippocampi of aged animals (>3 years) were reported [12, 19]. These differences may, at least in part, be caused by different rearing conditions (laboratory housing versus natural wildlife conditions) and it has to be considered that in their wildlife habitat the animals are exposed to stress, may suffer from hypertension, viral infections and diabetes, i.e. known risk factors contributing to the aetiology of AD and the early development of AD-type neuropathology.
Furthermore, the single amino-acid-difference between degus and humans at position 13 (histidine to arginine) affects a histidine residue (His13) which is crucial for aggregation and toxicity of Aβ. His13 is involved in early N-terminal β-sheet formation  and a substitution lowers aggregation propensity , neuronal binding , and cytotoxicity . Moreover, His13 is involved in the coordination of metal ions  and methylation or substitution by arginine, as seen in degus, lowers the affinity for metal ions and thus depletes aggregation [38–40] and attenuates toxicity [41, 42] of Aβ.
Two other species which are related to degus share a similar Aβ sequence, but, despite higher life expectancies, lack the neuropathological features as reported for degus. Naked mole rats (Heterocephalus glaber) have the identical Aβ sequence (see Fig. 1) and an exceptional lifespan of more than 30 years . Although young naked mole rats naturally exhibit pronounced oxidative stress  and Aβ levels similar to 3xTg-AD mice [34, 43], they do not develop amyloid plaques with age . Furthermore, naked mole rats even present with high levels of phosphorylated tau without any tangle formation . In Guinea pigs (Cavia porcellus), with a human identical Aβ sequence (see Fig. 1) and a lifespan similar to degus (average 5–7 ), dense amyloid deposits do not occur , despite similar APP processing [46, 47] and high β–secretase activity .
The additional screening for tau deposition, the second aggregating protein in AD, revealed similar intracellular reactivity in young and aged degus using phosphoepitope-specific antibodies AT8 and AT180. AT100 staining showed the previously described, unspecific nuclear localization . Biochemical analysis did not reveal an age-dependent increase of total, insoluble or phosphorylated tau (Fig. 7). Some variability observed in the levels of total tau or insoluble tau could hint subsets with different aggregation propensities but the very same animals did not exhibit tau pathology in IHC, and larger number of animals would be needed to identify the existence of such subsets. Hence, no evidence for a pathological deposition of tau could be detected in the examined animals.
The animals used in a variety of studies were collected from different sources [13, 48, 49], including animals caught in the wild [12, 50], the latter does usually not allow a precise age determination and thus hinders precisely controlled analyses. However, standardised housing conditions as used for the degus examined in the present study seem to prevent the development of ‘AD-like’ pathology described for wild-caught animals. Nonetheless, it would be fascinating to decipher the factors inducing the histopathological and biochemical changes in degus previously described [12, 13, 15]. Moreover, not only the particular species or the specific amino acid sequence seems influence the extent of amyloid deposition, but the genetic background likewise enfolds a strong effect . As degus are not yet an established research model, they lack a defined, stable and characterized inbred genetic background.
An interesting approach of separating old degus with severely aberrant behaviour as disease model takes high individual variability into account and indicates that ‘AD-like’ pathology might not necessarily develop in old degus. However, even in this selected subgroup with increased levels of inflammatory and oxidative stress markers, no correlation between altered behaviour and specific neuropathological symptoms could be established . The stated impairments of spatial memory and cognition in aged degus  may therefore be just a part of the normal aging process, since physiologic aging is linked to significant impairments in memory , cognition  and hippocampal long-term potentiation  in mice as well. Thus, symptoms of normal aging may not be misinterpreted to model AD.
Octodon degus was re-evaluated in the context of existing rodent AD models and human AD pathology. Performing immunohistological and molecular analyses of young and aged animals, we were able to show exclusively normal age-related cortical changes without indications for extensive degeneration as seen in patients with dementia and transgenic AD mice. Neither significant neuronal loss nor enhanced microglial activation were observed in aged animals of our degu population. Furthermore, no amyloid accumulation or tangle formation as seen in sporadic Alzheimer’s disease patients could be determined. Phosphoepitope-specific antibodies against tau species displayed similar intracellular neuronal reactivity in both, young and aged degus.
Moreover, we highlighted some previous results, which stand in contrast to the assumption of degus as natural AD model and seem to be thus far neglected. Bearing that in mind, assessment of degus as AD models should be meticulously done and receive particular attention. Currently, it is not clear if unnoticed environmental or rearing factors might play a role in triggering AD-like neuropathology. Therefore, we conclude that presently, the rodent Octodon degus is neither a superior model which is more suitable than other frequently used rodent models nor a ‘natural’ model of Alzheimer’s disease in general.
The work was financed by the following grants to J.P. (Deutsche Forschungsgemeinschaft DFG PA930/9, DFG PA930/12; VIAA Latvia NFI/R/2014/023; Leibniz Society SAW-2015-IPB-2; HelseSØ No:2016062; Norsk forskningsrådet: NFR251290, NFR246392, NFR248772, JPND NeuroGEM NFR247179, JPND PROP-AD NFR260786), K.B. (German-Israeli Foundation for Scientific Research and Development (GIF), BMBF Grants UBICA, TRANS-GEN). and C.K. (BMBF #01GQ1422A EU-FP7 MC-ITN IN-SENS #607616).
JS, MK, KP, CS conducted investigations, wrote manuscript; TB conducted investigations; RM, AMS, CK: conducted experiments, wrote manuscript; KB provided O. degu cohort, wrote manuscript; JP planned study, conducted investigations, wrote manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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