p25/Cyclin-Dependent Kinase 5 Induces Production and Intraneuronal Accumulation of Amyloid βIn Vivo

Abstract

Aberrant processing of the amyloid precursor protein (APP) and the subsequent accumulation of amyloid ␤ (A␤) peptide has been widely established as a central event in Alzheimer's disease (AD) pathogenesis. The sequential cleavage steps required for the generation of A␤ are well outlined; however, there is a relative dearth of knowledge pertaining to signaling pathways and molecular mechanisms that can modulate this process. Here, we demonstrate a novel role for p25/cyclin-dependent kinase 5 (Cdk5) in regulating APP processing, A␤ peptide generation, and intraneuronal A␤ accumulation in inducible p25 transgenic and compound PD-APP transgenic mouse models that demonstrate deregulated Cdk5 activity and a neurodegenerative phenotype. Induction of p25 resulted in enhanced forebrain A␤ levels before any evidence of neuropathology in these mice. Intracellular A␤ accumulated in perinuclear regions and distended axons within the forebrains of these mice. Evidence for modulations in axonal transport or ␤-site APP cleaving enzyme 1 protein levels and activity are presented as mechanisms that may account for the A␤ accumulation caused by p25/Cdk5 deregulation. Collectively, these findings delineate a novel pathological mechanism involving aberrant APP processing by p25/Cdk5 and have important implications in AD pathogenesis.

Suppression of Mutant Huntingtin Aggregate Formation by Cdk5/p35 through the Effect on Microtubule Stability

“…As a result of reduced Cdk5 activity, MTs may be overstabilized, or transport on MTs may be biased in a particular direction, resulting in higher local concentrations of mhtt in neurons of HD patients. In contrast, it is well known that abnormal activation of Cdk5 in neurons causes hyperphosphorylation of tau, possibly leading to aggregation of tau and then to neuronal cell death in Alzheimer's disease (Patrick et al, 1999;Noble et al, 2003;Cruz et al, 2006). Thus, proper regulation of Cdk5 kinase activity may be necessary for neuronal survival.…”

7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, Reverses Memory Deficits and BACE1 Elevation in a Mouse Model of Alzheimer's Disease

“…Multiple mechanisms are recently proposed to mediate the upregulation of BACE1 associated with AD. Those include the increased phosphorylation of the translation initiation factor eIF2a Devi and Ohno, 2010b;O'Connor et al, 2008), caspase-3-dependent inactivation of GGA3 leading to decreased lysosomal degradation of BACE1 (Sarajarvi et al, 2009;Tesco et al, 2007), changes in microRNA expression profiles (Hebert et al, 2008;Wang et al, 2008), p25/cyclin-dependent kinase 5 pathways (Cruz et al, 2006;Wen et al, 2008), calpain activation (Liang et al, 2010), the receptor for advanced glycation end products (RAGE) (Cho et al, 2009;Guglielmotto et al, 2010), and oxidative stress or related signals such as nuclear factor-kB, c-Jun N-terminal kinase, and p38 MAPK (Chen et al, 2011;Chen et al, 2008;Coma et al, 2008;Xiong et al, 2007). Further study will be needed to determine the molecular pathways by which activation of BDNF-TrkB signaling may counteract the BACE1 elevation in 5XFAD mice.…”

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

“…A␤ peptides are generated by successive proteolysis of ␤-amyloid precursor protein (APP), a large transmembrane glycoprotein that is initially cleaved by the ␤-site APPcleaving enzyme 1 (BACE1) and subsequently by ␥-secretase in the transmembrane domain (De Strooper et al, 1998;Vassar et al, 1999;Edbauer et al, 2003). Phosphorylation of APP at its C-terminal Thr668 facilitates its processing (Cruz et al, 2006). Although the aggregated A␤ peptides are believed to play a central role in AD pathology (Chen et al, 2000;Apelt and Schliebs, 2001;Götz et al, 2001;Walsh et al, 2002), the cause of AD remains elusive.…”