Lessons from the analysis of nonhuman primates for understanding human aging and neurodegenerative diseases

Animal models are necessary tools for solving the most serious challenges facing medical research. In aging and neurodegenerative disease studies, rodents occupy a place of choice. However, the most challenging questions about longevity, the complexity and functioning of brain networks or social intelligence can almost only be investigated in nonhuman primates. Beside the fact that their brain structure is much closer to that of humans, they develop highly complex cognitive strategies and they are visually-oriented like humans. For these reasons, they deserve consideration, although their management and care are more complicated and the related costs much higher. Despite these caveats, considerable scientific advances have been possible using nonhuman primates. This review concisely summarizes their role in the study of aging and of the mechanisms involved in neurodegenerative disorders associated mainly with cognitive dysfunctions (Alzheimer’s and prion diseases) or motor deficits (Parkinson’s and related diseases)

Diversity of Y-chromosomal and mtDNA Markers Included in Mediscope Chip within Two Albanian Subpopulations from Croatia and Kosovo: Preliminary Data

The aim of this preliminary study is to analyze genetic specificity of Kosovo Albanians comparing with neighboring populations using new genetic tool - MEDISCOPE gene chip, to investigate the feasibility of this approach. We collected 37 DNA samples (9 Croats, 17 Albanians from Croatia and 11 Albanians from Kosovo) from unrelated males born in Croatia and Kosovo. Additionally, samples were expanded with female individuals and mtDNA analysis included a total of 61 samples (15 Croats, 23 Albanians from Croatia and 23 Albanians from Kosovo). This pilot study suggests that the usage of the MEDISCOPE chip could be recognized as an efficient tool within recognition of the population genetic specificity even within extremely small sample size

Branched-chain amino acid database integrated in MEDIPAD software as a tool for nutritional investigation of mediterranean populations

Branched-chained amino acids (BCAA) are essential dietary components for humans and can act as potential biomarkers for diabetes development. To efficiently estimate dietary intake, we developed a BCAA database for 1331 food items found in the French Centre d'Information sur la Qualité des Aliments (CIQUAL) food table by compiling BCAA content from international tables, published measurements, or by food similarity as well as by calculating 267 items from Greek, Turkish, Romanian, and Moroccan mixed dishes. The database embedded in MEDIPAD software capable of registering 24 h of dietary recalls (24HDR) with clinical and genetic data was evaluated based on archived 24HDR of the Saint Pierre Institute (France) from 2957 subjects, which indicated a BCAA content up to 4.2 g/100 g of food and differences among normal weight and obese subjects across BCAA quartiles. We also evaluated the database of 119 interviews of Romanians, Turkish and Albanians in Greece (27⁻65 years) during the MEDIGENE program, which indicated mean BCAA intake of 13.84 and 12.91 g/day in males and females, respectively, comparable to other studies. The MEDIPAD is user-friendly, multilingual, and secure software and with the BCAA database is suitable for conducting nutritional assessment in the Mediterranean area with particular facilities for food administration

Old Gray Mouse Lemur Behavior, Cognition, and Neuropathology

International audienceNonhuman primate models are required to understand aging and age-related pathologies. The gray mouse lemur Microcebus murinus, a small prosimian primate, develops age-dependent deficits that are comparable to the decline observed during normal and pathological aging in humans. Importantly, not all old gray mouse lemurs are equally affected by age-related behavioral and cognitive problems. Some are profoundly impaired, while others perform as well as younger animals. Moreover, brain atrophy is detected only in some animals and thus appears to be an age-related pathological condition more than an inevitable effect of age. Finally, a subset of aged animals display neuropathological lesions observed also in Alzheimer's disease: β-amyloid deposition mainly in diffuse plaques and tau protein aggregation in some pyramidal neurons of the entorhinal cortex and hippocampus. Overall, these age-related changes indicate that gray mouse lemurs could be used as a potential translational model to study age-associated deficits and disorders

GIGYF2 gene disruption in mice results in neurodegeneration and altered insulin-like growth factor signaling

Grb10-Interacting GYF Protein 2 (GIGYF2) was initially identified through its interaction with Grb10, an adapter protein that binds activated IGF-I and insulin receptors. The GIGYF2 gene maps to human chromosome 2q37 within a region linked to familial Parkinson's disease (PARK11 locus), and association of GIGYF2 mutations with Parkinson's disease has been described in some but not other recent publications. This study investigated the consequences of Gigyf2 gene disruption in mice. Gigyf2 null mice undergo apparently normal embryonic development, but fail to feed and die within the first 2 post-natal days. Heterozygous Gigyf2+/− mice survive to adulthood with no evident metabolic or growth defects. At 12–15 months of age, the Gigyf2+/− mice begin to exhibit motor dysfunction manifested as decreased balance time on a rotating horizontal rod. This is associated with histopathological evidence of neurodegeneration and rare intracytoplasmic Lewy body-like inclusions in spinal anterior horn motor neurons. There are α-synuclein positive neuritic plaques in the brainstem and cerebellum, but no abnormalities in the substantia nigra. Primary cultured embryo fibroblasts from Gigyf2 null mice exhibit decreased IGF-I-stimulated IGF-I receptor tyrosine phosphorylation and augmented ERK1/2 phosphorylation. These data provide further evidence for an important role of GIGYF2 in age-related neurodegeneration and IGF pathway signaling

Characterization of cardiac pacemaker activity in the primate lemur Microcebus murinus

Abstract Mouse lemur ( Microcebus murinus ) is one of the smallest and more ancestral primates known so far. It is an emerging model of senescence and neurodegeneration, thanks to its genetic proximity to humans compared to rodents. Thus, M. murinus could help to better understand cardiac physiology in humans. Nevertheless, the cardiac physiology of M. murinus is still unknown. We had the opportunity to characterize cardiac activity in mouse lemurs, focusing on the pacemaker activity generation by the Sinoatrial node (SAN). Notably, we recorded cardiac activity in animals, isolated hearts, cardiac tissues and SAN pacemaker myocytes. We showed that the heart rate (HR) of mouse lemurs lays in between that of mice and rats, the rodents of closer size with M. murinus . Conversely, the ventricular depolarization of this lemur is more similar to humans or large mammals rather than small rodents. In the SAN myocytes of M. murinus we recorded three of the main ionic currents involved in the SAN pacemaker activity of vertebrates, I f , I Ca,L and I Ca,T , and the expression of the SAN marker HCN4. In parallel, we characterize skeletal muscle-derived stem cells (MDSCs) from M. murinus . These MDSCs differentiate in vitro in automatic cells showing a pacemaker-like (PML) phenotype. These cells show common features with native SAN myocytes and could be useful to test pharmacological strategies to modulate pacemaker activity. In conclusion, the characterization of M. murinus HR and SAN pacemaker activity, together with the generation of PML cells pave the way for comparative studies of cardiac physiology in primates and pharmacologic tests to handle disease of cardiac automaticity

Characterization of sinoatrial automaticity in Microcebus murinus to study the effect of aging on cardiac activity and the correlation with longevity

International audienceMicrocebus murinus, or gray mouse lemur (GML), is one of the smallest primates known, with a size in between mice and rats. The small size, genetic proximity to humans and prolonged senescence, make this lemur an emerging model for neurodegenerative diseases. For the same reasons, it could help understand how aging affects cardiac activity. Here, we provide the first characterization of sinoatrial (SAN) pacemaker activity and of the effect of aging on GML heart rate (HR). According to GML size, its heartbeat and intrinsic pacemaker frequencies lie in between those of mice and rats. To sustain this fast automaticity the GML SAN expresses funny and Ca2+ currents (If, ICa,L and ICa,T) at densities similar to that of small rodents. SAN automaticity was also responsive to β-adrenergic and cholinergic pharmacological stimulation, showing a consequent shift in the localization of the origin of pacemaker activity. We found that aging causes decrease of basal HR and atrial remodeling in GML. We also estimated that, over 12 years of a lifetime, GML generates about 3 billion heartbeats, thus, as many as humans and three times more than rodents of equivalent size. In addition, we estimated that the high number of heartbeats per lifetime is a characteristic that distinguishes primates from rodents or other eutherian mammals, independently from body size. Thus, cardiac endurance could contribute to the exceptional longevity of GML and other primates, suggesting that GML's heart sustains a workload comparable to that of humans in a lifetime. In conclusion, despite the fast HR, GML replicates some of the cardiac deficiencies reported in old people, providing a suitable model to study heart rhythm impairment in aging. Moreover, we estimated that, along with humans and other primates, GML presents a remarkable cardiac longevity, enabling longer life span than other mammals of equivalent size