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. 2013 Oct;34(10):2352-60.
doi: 10.1016/j.neurobiolaging.2013.03.032. Epub 2013 Apr 22.

Amyloid Beta and the Longest-Lived Rodent: The Naked Mole-Rat as a Model for Natural Protection From Alzheimer's Disease

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Amyloid Beta and the Longest-Lived Rodent: The Naked Mole-Rat as a Model for Natural Protection From Alzheimer's Disease

Yael H Edrey et al. Neurobiol Aging. .
Free PMC article

Abstract

Amyloid beta (Aβ) is implicated in Alzheimer's disease (AD) as an integral component of both neural toxicity and plaque formation. Brains of the longest-lived rodents, naked mole-rats (NMRs) approximately 32 years of age, had levels of Aβ similar to those of the 3xTg-AD mouse model of AD. Interestingly, there was no evidence of extracellular plaques, nor was there an age-related increase in Aβ levels in the individuals examined (2-20+ years). The NMR Aβ peptide showed greater homology to the human sequence than to the mouse sequence, differing by only 1 amino acid from the former. This subtle difference led to interspecies differences in aggregation propensity but not neurotoxicity; NMR Aβ was less prone to aggregation than human Aβ. Nevertheless, both NMR and human Aβ were equally toxic to mouse hippocampal neurons, suggesting that Aβ neurotoxicity and aggregation properties were not coupled. Understanding how NMRs acquire and tolerate high levels of Aβ with no plaque formation could provide useful insights into AD, and may elucidate protective mechanisms that delay AD progression.

Keywords: 3xTg-AD mice; Aggregation; Alzheimer's disease; Amyloid beta; Heterocephalus glaber; Naked mole-rat; Neuronal toxicity.

Conflict of interest statement

Disclosure statement

The authors state that they have nothing to disclose, and that there are no potential conflicts of interest.

Figures

Fig. 1
Fig. 1
Slight species differences in Aβ sequence lead to marked differences in Aβ aggregation properties. Note positions 5, 10, and 13 of the Aβ sequence, where species differences between human and mouse Aβ are evident. Only position 13 differs between human and NMR (histidine and arginine, respectively) (A). Nevertheless, NMR and mouse/rat Aβ have a lower propensity to aggregate than the human form (ANOVA, p = 0.011), as measured by the change in kinetic florescence of ThT (B). Data are presented as mean ± SEM for triplicates of each sample.
Fig. 2
Fig. 2
Grain analysis data reveal that aggregation properties depend on sequence and incubation conditions. Grain analysis data extracted from 3 fields for both human and NMR Aβ1–42 examined with AFM OriginPro 8.6 (OriginLab Corp., Northampton, MA) reveal significant differences between both samples as represented by distribution of footprint parameter (area covered by a particle). At time 0, no significant changes are evident between human and NMR Aβ1–42. (t test, p = 0.9) (A). After 1 hour incubation at room temperature, human Aβ1–42 aggregation is beginning to diverge from the NMR sample (t test, p = 0.69) (B). After 48 hours’ incubation at 37 °C, human and NMR Aβ1–42 show 2 discrete patterns of aggregation (C). Percentage of total area coverage by aggregates (particles) differs drastically (t test, p ≤ 0.00001) between human (hatched bars) and NMR (white bars) after 48 hours of incubation. The coverage after 0 or 1 hour does not differ significantly (D). Data presented as mean ± SEM.
Fig. 3
Fig. 3
Aggregation and neurotoxicity properties of NMR Aβ are uncoupled. AFM images reveal differences in polymerization of human and NMR Aβ1–42. The presented raw topography images of 750 × 750-nm fields were zoomed in from 1-µm2 fields. Human Aβ1–42 (A) and NMR Aβ1–42 (B) at time 0 show a similar pattern of aggregation. After 1 hour at 37 °C, a divergent pattern begins to emerge (C and D). After 48 hours’ incubation at 37 °C, a striking difference is evident between both samples with greater aggregation evident in the human Aβ1–42 (E) compared to the NMR Aβ1–42 (F). The gray scale represents the height of particles, with black representing the background (lowest areas) and light shades representing Aβ polymers. Neurotoxicity of NMR Aβ is similar to that of human Aβ (G). Mouse primary neurons were pretreated with or without (control) 10 µmol/L of either form of Aβ, and cell viability was assessed with MTT assay 24 hours after treatment. A decline of 18% cell viability was apparent when Aβ was used, regardless of the sequence used (NMR or human). Data presented are mean ± SEM, as normalized to controls.
Fig. 4
Fig. 4
Levels of Aβ are detectable in young NMRs and are comparable to those of young 3xTg-AD mice. Young NMRs (2–9 years old; n = 15; gray-shaded circles) show levels of Aβ similar to those of young (8-month-old; n = 3; open squares) 3xTg-AD mice. Six of the samples for soluble Aβ1–40 had undetectable levels (A). Soluble Aβ1–40 and soluble Aβ1–42 (B) were not significantly different from those of 8-month-old 3xTg-AD mice (t test, p = 0.26 and p = 0.92, respectively). Levels of insoluble Aβ1–40 were also similar, with 1 NMR outlier as calculated by having levels more than 2 SDs higher than the average is shown on the graph. It was not included to calculate average levels or statistical analysis (t test, p = 0.69) (C). Levels of insoluble Aβ1–42 were also similar to those of 3xTg-AD mice (t test, p = 0.77) (D). All data points obtained in our experiments are represented, and the average per species appears as a bar.
Fig. 5
Fig. 5
Levels of Aβ do not increase with age in NMRs. Levels of NMR (gray circles) soluble Aβ1–40 (A) and Aβ1–42 (B) did not increase with age (2–26 years; gray circles y=−16.48x + 1274.25; R2 = 0.0162, p = 0.44; y = 14.819x + 264.187; R2 = 0.0539, p = 0.155, respectively). Similarly, levels of insoluble Aβ1–40 (C) did not increase with age (y = −0.806x + 166.723; R2 = 0.0003, p = 0.914). In contrast, although insoluble Aβ1–42 (D) levels in young animals are comparatively very low, because of 1 very high value in the aged group, a significant positive correlation with age, was apparent (y = 23.53x + 1.314; R2 = 0.136, p = 0.022, respectively); however, if this 1 outlier is ignored, there was no significant relationship (y = 12.70x + 108.96; R2 = 0.094, p = 0.112). In all cases, NMR levels are within similar range to those of young (8-month-old) 3xTg-AD mice (open squares). All data points obtained in our experiments are represented; n = 39 for NMRs, n = 3 for 3xTg-AD mice.
Fig. 6
Fig. 6
No age-related change in APP processing with no evidence for senile plaques. C83 and C99 are the C-terminal fragments that remain after APP processing. The former is a footprint of the non-amyloidogenic pathway, whereas the latter implies an amyloidogenic event. Neither C83 (A) nor C99 (B) changed significantly among young (2 years), older (10–15 years), and the oldest (20+ years) NMRs (ANOVA F = 2.572, p = 0.171; F = 2.149, p = 0.212, respectively). A representative immunoblot of C83 and C99 is shown (C, top) with the corresponding loading control (C, bottom). In all age groups, the ratio between C83 and C99, however, suggests that there are more non-amyloidogenic events than amyloidogenic ones, providing some protection against Aβ production. Immunostaining with 6E10 antibody does not reveal plaques in NMRs. Note that some intraneuronal staining appears; staining with 4G8 antibody revealed the same pattern and is therefore not shown here. No plaques detected in low (D) or high (F) magnification of a 29-year-old NMR. For control purposes, immunohistochemistry was performed in tandem with an 18-month-old 3xTg-AD mouse. Low (E) and high (G) magnification clearly shows Aβ plaques (arrows).

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