• 2018-07
  • 2018-10
  • 2018-11
  • Aside from the importance of producing plaque and


    Aside from the importance of producing plaque and tangle pathology in a dish, the findings by Kim, Tanzi, and colleagues also re-emphasize the importance of exploring the genetics underlying AD. Although many FAD mutations in and have been well-characterized over the past 20years, the advent of more sophisticated sequencing techniques allows for the identification of an infinite number of genetic changes associated with AD which could not only give insight into disease pathogenesis but also identify novel therapeutic candidates. Genome-wide association studies (GWAS) have identified at least 20 new loci involved in the increased risk for developing AD (). For example, recent whole-exome and whole-genome wide sequencing strategies identified mutations in the gene as conferring an increased risk for AD by 3.4-fold (). TREM2, or triggering receptor expressed on myeloid phosphodiesterase inhibitor 2, is a transmembrane protein expressed by myeloid cells, including microglia and peripheral monocytes. Although endogenous ligands for TREM2 remain unknown, TREM2 regulates phagocytosis and the neuroinflammatory response to pathology within the brain. The identification of mutations provides further confirmation that neuroinflammation, specifically microglial activation, is a significant component of AD pathogenesis and is an important component of the comprehensive treatment of AD. Although the role of TREM2 expression on microglial function in the context of Aβ and tau is still up for debate (), the importance of GWAS for furthering both the basic understanding of AD as well as the importance in elucidating new therapeutic avenues to pursue is unequivocal.
    Down syndrome (DS) was first described in 1866 by John Langdon Down and it is now recognized as the most common chromosomal disorder and cause of intellectual disability (). Despite its prevalence (roughly 1 in 1000 births), the cause of the disease was not identified until 1959 when karyotyping enabled the identification of trisomy 21 as responsible for the majority of DS cases (). The complete sequence of chromosome 21 was determined in the year 2000 (). Yet, as researchers have discovered time and again, knowledge of an organism\'s genetic sequence does not necessarily translate into a precise understanding of molecular and cellular processes. Almost sixty years have passed since the cause of the disease was identified; yet the mechanisms underlying DS remain obscure. In this issue of , Najas et al. expand our knowledge of DS by showing that the dosage of the evolutionarily conserved tyrosine kinase Dyrk1a, encoded by a gene located on chromosome 21 and triplicated in DS, alters the cell cycle, and hence the fate, of neural stem cells (). During mammalian corticogenesis, radial glial (RG) cells primarily divide to either expand their own population or produce intermediate progenitors (IPs). IPs have limited proliferative potential and predominantly generate neurons (). Interestingly, both the regulation of the switch of RG cells from expansion to generation of IPs as well as the proliferative potential of IPs are intimately linked to cell cycle length (). Specifically, the G1 phase is known to lengthen as neurogenesis progresses and overexpression of cell cycle regulators such as cyclin D1 shortens G1 and promotes proliferative (at the expense of neurogenic) divisions (). Changes in cell cycle regulation and cell fate change of neural progenitors were already reported in trisomic mouse models of DS () and it was also known that Dyrk1a could somehow influence both cell cycle progression and neurogenesis in vitro and phosphodiesterase inhibitor in vivo (). However, these previous studies could not assess the dose-dependent effect of Dyrk1a and quantify its effects on specific phases of the cell cycle. To address this, Najas and colleagues generated a number of mouse lines in which either three or one allele of Dyrk1a was present. Focusing on the developing brain, they observed decreased nuclear levels of cyclin D1 in the mouse line with three alleles while, conversely, finding more in the single-allele, haploinsufficient Dyrk1a line. Explaining this phenotype, Dyrk1a was found to phosphorylate cyclin D1 in vitro and likely disrupt its trafficking and degradation. Consistent with a decrease in the levels of cyclin D1, the authors found that an increase in the Dyrk1a gene dosage caused a lengthening of both G1 and S phases. This correlated with a transient increase in IPs followed by their premature depletion, which resulted in a transient increase in neurons at mid-neurogenesis followed by an overall reduction in the total neuronal output of the postnatal brain. Haploinsufficient mice displayed a converse phenotype, shedding light on the mechanistic link between gene-dosage of Dyrk1a and developmental malformations associated with DS.