All in the Family: How the APPs Regulate Neurogenesis

Recent intriguing evidence suggests that metabolites of amyloid precursor protein (APP), mutated in familial forms of Alzheimer’s disease (AD), play critical roles in developmental and postnatal neurogenesis. Of note is soluble APPα (sAPPα) that regulates neural progenitor cell proliferation. The APP family encompasses a group of ubiquitously expressed and evolutionarily conserved, type I transmembrane glycoproteins, whose functions have yet to be fully elucidated. APP can undergo proteolytic cleavage by mutually exclusive pathways. The subtle structural differences between metabolites generated in the different pathways, as well as their equilibrium, may be crucial for neuronal function. The implications of this new body of evidence are significant. Miscleavage of APP would readily impact developmental and postnatal neurogenesis, which might contribute to cognitive deficits characterizing Alzheimer’s disease. This review will discuss the implications of the role of the APP family in neurogenesis for neuronal development, cognitive function, and brain disorders that compromise learning and memory, such as AD

Soluble amyloid precursor protein: a novel proliferation factor of adult progenitor cells of ectodermal and mesodermal origin

Introduction: Soluble amyloid precursor protein a (sAPPa) is a proteolyte of APP cleavage by a-secretase. The significance of the cleavage and the physiological role of sAPPa are unknown. A crystal structure of a region of the amino terminal of sAPPa reveals a domain that is similar to cysteine-rich growth factors. While a previous study implicates sAPPa in the regulation of neural progenitor cell proliferation in the subventricular zone of adult mice, the ubiquitous expression of APP suggests that its role as a growth factor might be broader. Methods: sAPPa and a-secretase activities were determined in neural progenitor cells (NPCs), mesenchymal stem cells (MSC) and human decidua parietalis placenta stem cells (hdPSC). Inhibition of a-secretase was achieved by treatment with the matrixmetalloproteinase inhibitor GM6001, and proliferation was determined using clonogenic and immunocytochemical analysis of cell-lineage markers. Recovery of proliferation was achieved by supplementing GM6001-treated cells with recombinant soluble APPa. Expression of APP and its cellular localization in the subventricular zone was determined by Western blot and immunohistochemical analyses of APP wild type and knockout tissue. Alterations in pERK and pAKT expression as a function of soluble APPa production and activity in NPCs were determined by Western blot analysis. Results: Here we show that sAPPa is a proliferation factor of adult NPCs, MSCs and hdpPSC. Inhibition of asecretase activity reduces proliferation of these stem cell populations in a dose-dependent manner. Stem cell proliferation can be recovered by the addition of sAPPa in a dose-dependent manner, but not of media depleted of sAPPa. Importantly, sAPPa operates independently of the prominent proliferation factors epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), but in association with ERK signaling and MAP-kinase signaling pathways. Levels of sAPPa and putative a-secretase, ADAM10, are particularly high in the subventricular zone of adult mice, suggesting a role for sAPPa in regulation of NPCs in this microenvironment. Conclusions: These results determine a physiological function for sAPPa and identify a new proliferation factor of progenitor cells of ectodermal and mesodermal origin. Further, our studies elucidate a potential pathway for sAPPa signaling through MAP kinase activation

Soluble Amyloid Precursor Protein Regulates Neurogenesis: Implications for Brain Repair

Amyloid precursor protein (APP) has been studied extensively in the pathophysiology of Alzheimer’s disease due to the fact that mutations in APP are causative of familial forms of the disease. However, the physiological significance of the protein has yet to be fully elucidated. APP undergoes sequential metabolism through two distinct pathways involving three enzymatic cleavage events via enzymes termed α-, β, and γ-secretase. These cleavage events produce a number of intra- and extra-cellular metabolites that add complexity to the potential physiological function of APP. α-secretase cleavage produces a soluble extracellular metabolite, soluble amyloid precursor protein alpha (sAPPα), that has been previously shown to have trophic characteristics and contain a cysteine-rich growth factor like domain. In the adult brain, neural progenitor cells (NPC) represent a proliferating population of cells that have the ability to form new neurons in discrete regions. These NPC have been shown to have binding sites for sAPP. In Alzheimer’s disease and normal aging, there is a dramatic decline in the adult neurogenesis. We hypothesized that sAPPα is a growth factor for NPC of the adult brain and alterations in the metabolism of APP/sAPPα during normal aging or in Alzheimer’s disease could contribute to stem cell senescence. In this work we show that sAPPα potently stimulates the proliferation of NPC following α-secretase inhibition independently of epidermal growth factor or basic fibroblast growth factor. Further, sAPPα induces phosphorylation of extracellular signal-regulated kinase (Erk) and transcription of genes associated with cell cycle, neurogenesis and energy metabolism. The soluble metabolite derived from the alternative, pathological, cleavage pathway of APP, sAPPβ, shows only slight proliferative qualities in NPC suggesting that alterations in the normal cleavage pattern of APP could underlie neurogenic impairments in Alzheimer’s disease. Finally, we show that sAPP levels decline with age in a manner that correlates with the timing of neurogenic decline and that a single intracerebroventricular injection of sAPPα is sufficient to ameliorate aging-linked deficits in neurogenesis. Taken together, these results suggest that sAPPα is a proliferation factor for NPC of the adult brain whose decline in aging or Alzheimer’s disease could contribute to neurogenic deficits

All in the family: how the APPs regulate neurogenesis

Recent intriguing evidence suggests that metabolites of amyloid precursor protein(APP), mutated in familial forms of Alzheimer’s disease(AD), play critical roles indevelopmental and post natal neurogenesis. Of note is soluble APPα (sAPPα) that regulates neural progenitor cell proliferation. The APP family encompasses a group of ubiquitously expressed and evolutionarily conserved, type I transmembrane glycoproteins, whose functions have yet to be fully elucidated. APP can undergo proteolytic cleavage by mutually exclusive pathways. The subtle structural differences between metabolites generated in the different pathways, as well as thei requilibrium, maybe crucial for neuronal function. The implications of this newbody of evidence are significant. Miscleavage of APP would readily impact developmental and postnatal neurogenesis, which might contribute to cognitive deficits characterizing Alzheimer’s disease. This review will discuss the implications of the role of the APP family in neurogenes is for neuronal development, cognitive function, and brain disorders that compromise learning and memory, such as AD

Moose, caribou and fire: have we got it right yet?

Natural disturbance plays a key role in shaping community dynamics. Within Canadian boreal forests, the dominant form of natural disturbance is fire, and its effects are thought to influence the dynamics between moose (Alces alces (Linnaeus, 1758)) and the boreal ecotype of woodland caribou (Rangifer tarandus caribou (Gmelin, 1788)). Boreal caribou are considered “threatened” and population declines are attributed, at least in part, to disturbance-mediated apparent competition (DMAC) with moose. Here, we tested a primary prediction of the DMAC hypothesis: that moose respond positively to burns within and adjacent to the caribou range. We assessed moose selection for ≤25-year-old burns (when selection is predicted to be strongest) at multiple spatial scales and evaluated whether moose density was correlated with the extent of ≤40-year-old burns (a time frame predicted to negatively affect caribou). Against expectation, moose showed avoidance and low use of ≤25-year-old burns at all scales, regardless of burn age, season, and type of land cover burned. These findings mirrored the demographic response, as we found no correlation between ≤40-year-old burns and moose density. By contradicting the prevailing hypothesis linking fires to caribou population declines, our results highlight the need to understand regional variation in disturbance impacts on caribou populations.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author