Distribution of lithostathine in the mouse lemur brain with aging and Alzheimer's-like pathology

Abstract

We analyzed the cellular distribution of the pancreatic inflammatory protein lithostathine and its receptor EXTL3 in the brain of the lemurian primate Microcebus murinus which develops amyloid deposits along with aging. In adult animals (2-4.5 year-old), lithostathine and EXTL3 immunoreactivities were largely distributed in the whole brain, and more intensively in almost all cortical layers and hippocampal formation. Lithostathine was observed in the perikarya and neurites of cortical neurons but also in glial cells in the border of the ventricle and the corpus callosum.In healthy aged animals (8-13 year-old), highest densities of lithostathine containing cells were observed, mainly in occipital and parietal cortex. In aged animals with A deposits, the increase in lithostathine immunoreactivity was lower as compared with aged animals. Noteworthly, lithostathine-immunopositive cells did almost never colocalize with A plaques. In conclusion, lithostathine immunoreactivity in adult Microcebus murinus appeared ubiquitous and particularly in visual, sensorial and cognitive brain areas. Immunoreactivity increased with aging and appeared markedly affect in neuropathological conditions. Its possible neuroprotection or neurodegeneration role in Alzheimer pathology deserves therefore to be investigated.

Regenerating Islet-derived 1α (Reg-1α) Protein Is New Neuronal Secreted Factor That Stimulates Neurite Outgrowth via Exostosin Tumor-like 3 (EXTL3) Receptor

“…Here, we used primary embryonic hippocampal neurons (E17.5; 2 days in vitro) and two cell lines (PC12 cells, which are derived from a rat pheochromocytoma and reversibly respond to NGF by induction of the neuronal phenotype, and N2a, which are derived from a neuroblastoma and belong to a neural lineage) to investigate the expression, localization, and functions of Reg-1␣ in nerve cells. We first show that Reg-1␣ is expressed in neuronal cells with perinuclear localization and a particularly strong expression at the membrane of the cell bodies and along neurites as reported recently for neurons from M. murinus brain (17). We then demonstrate that neurite outgrowth is stimulated by Reg-1␣ overexpression or addition of recombinant Reg-1␣, and it is reduced when Reg-1␣ is downregulated by siRNA.…”

“…In mouse embryos, EXTL3 mRNA is expressed in both the central and peripheral nervous system from E11.5 to E16.5, and its expression is developmentally regulated and contributes to brain development (13). In M. murinus, Reg-1␣ and its receptor EXTL3 are localized in the same pyramidal neurons of the hippocampus (17). Here, we show that Reg-1␣ co-localizes with EXTL3 at the cell membrane of neuronal cells, and we demonstrate that the effects of Reg-1␣ on neurite elongation are mediated at least in part through this receptor.…”

“…1D, lane 2). The specificity of the polyclonal anti-Reg-1␣ antibody was assessed previously (17,19), and it does not cross-react with other members of the family or with neuronal thread protein (11).…”

“…Moreover, in AD, elevated Reg-1␣ expression may reflect widespread aberrant neuritic sprouting correlated with synaptic disconnection and dementia (11,15,16). Recently, we have demonstrated that Reg-1␣ and its receptor EXTL3 are expressed in the cortical layer and hippocampal formation of Microcebus murinus brain and that Reg-1␣ expression increases in aged and AD-like animals (17). Interestingly, Reg-1␣ is highly susceptible to self-proteolysis and generates a C-terminal polypep-tide that is largely insoluble at physiological pH and readily polymerizes into fibrils (18 -20).…”

Primate aging in the mammalian scheme: the puzzle of extreme variation in brain aging

“…The differences between general aging changes and clinical disease may be described as eugeric vs. pathogeric age changes (Finch 1972). For example, in US-wide samples of the NHANES, fluid intelligence scores peak at about 25 years and decline progressively at about a Chimpanzee, 41 years , 59 years (Gearing et al 1994(Gearing et al , 1996, and 2 "aged," no age given (Gearing et al 1994); gorilla, 44 years (Kimura et al 2001); orangutans-28, 31, and 36 years (Gearing et al 1997); baboon (Schultz et al 2000); and lemur (Bons et al 2006;Kraska et al 2011;Marchal et al 2012) 0.5%/year up through age 70 (McArdle 2009;Salthouse 2009). Complex multi-tasking ("walking while memorizing") also declines progressively across middle age (Li et al 2001).…”