Linking cognition to amyloid-β burden in the brain of a non-human primate (Microcebus murinus)

In the non-human-primate (NHP) Microcebus murinus, the grey mouse lemur, many morphological, physiological, and cognitive traits are age-dependent, comparable to humans. Extensive studies on brain aging in different laboratory colonies of M. murinus demonstrated the natural development of pathological brain alterations in a sub-population of aged individuals, including hippocampal and septal atrophies, the aggregation of phosphorylated Tau protein, and deposits of amyloid-β peptide (Aβ) and its precursor. They may be markers of a neurodegenerative disease comparable to Alzheimer’s disease (AD) in humans. To further explore this hypothesis, we submitted aged individuals that took part in a cognitive study on visual pairwise discrimination (PD)/discrimination reversal (PDR) learning to neuro-immunohistochemistry (Aβ and Tau) once they had died from a natural death and investigated possible links between Aβ (and Tau) burden and cognitive performance. In total we trained 37 old grey mouse lemurs (12 males, 25 females; age range: 5-11 years) in a standardized, touchscreen-based PD/PDR task. Out of these 37 subjects, 20 completed the entire criterion-based PD/PDR training. Of the remaining 17 subjects, two died from a natural death during the course of the study, while 15 dropped out of the experiment as they failed to complete the pre-training procedure that precedes the actual PD/PDR task. Interestingly, where neuro immunohistochemistry was possible, we found that pre-training dropouts presented significantly more often with intraneuronal accumulations of Aβ as compared to NHPs that completed the pre-training (Fisher’s Exact Test, odds ratio estimate: 0.129; 95% confidence interval: 0.011, 0.868; p-value = 0.023). Performance in visual pairwise discrimination learning (number of trials to criterion), on the other hand, was linked to the quantity (low vs. high burden) of extracellular Aβ deposits in the cortex (Wilcoxon Rank Sum Tests, W = 52, p-value = 0.0196). A statement about the exact spatial pattern of the Aβ proteopathy at the time of cognitive testing cannot be made, as the histopathology was performed after subjects had died from a natural death, i.e. often a long time after the cognitive testing. Since intracellular Aβ depositions are considered to precede and catalyze AD-like extracellular proteopathology in both transgenic animal models and humans, it is possible that the linkage we found between extracellular Aβ burden at death and cognitive performance in the PD is also a reflection of intracellular Aβ burden at the time of testing. All tested animals proved negative for phosphorylated Tau. In summary, our study provides the first evidence for a direct link of a naturally developed cortical Aβ burden and cognitive performance in an NHP. To solve the matter of the exact link between intra- and extracellular Aβ burden and cognition in future studies on mouse lemur AD-like pathology, it will be necessary to combine cognitive testing with in vivo assessment of Aβ buildups in this species. However, the here-presented findings, together with recent methodological advances in mouse lemur genetics, in vivo imaging, and cross-species comparable cognitive testing, are in strong support for the idea that the grey mouse lemur is exceptionally suited as a natural NHP model in biomedical research, especially in the field of healthy and pathological brain aging.