Axonal degeneration in Alzheimer's disease: when signaling abnormalities meet the axonal transport system

Abstract

Alzheimer's disease (AD) is characterized by progressive, age-dependent degeneration of neurons in the central nervous system. A large body of evidence indicates that neurons affected in AD follow a dying-back pattern of degeneration, where abnormalities in synaptic function and axonal connectivity long precede somatic cell death. Mechanisms underlying dying-back degeneration of neurons in AD remain elusive but several have been proposed, including deficits in fast axonal transport (FAT). Accordingly, genetic evidence linked alterations in FAT to dying-back degeneration of neurons, and FAT defects have been widely documented in various AD models. In light of these findings, we discuss experimental evidence linking several AD-related pathogenic polypeptides to aberrant activation of signaling pathways involved in the phosphoregulation of microtubule-based motor proteins. While each pathway appears to affect FAT in a unique manner, in the context of AD, many of these pathways might work synergistically to compromise the delivery of molecular components critical for the maintenance and function of synapses and axons. Therapeutic approaches aimed at preventing FAT deficits by normalizing the activity of specific protein kinases may help prevent degeneration of vulnerable neurons in AD.

Keywords: Alzheimer's disease; Amyloid; ApoE; Axonal transport; CK2; Dynein; GSK3; Kinase; Kinesin; Phosphatase; Presenilin; Signaling; Synapse; Tau.

Fig. 1

Phosphoregulation of motor protein complexes that mediate fast axonal transport (FAT). (A) Biochemically heterogeneous forms of conventional kinesins are regulated through numerous kinases that phosphorylate specific motor protein subunits and regulate specific functional activities. For example, the microtubule-binding activity of kinesin heavy chains (KHCs) is inhibited by c-Jun N-terminal kinase 3 (JNK3) and p38-mediated phosphorylation. In contrast, both glycogen synthase kinase 3 (GSK3) and casein kinase 2 (CK2) phosphorylate kinesin light chains (KLCs), promoting dissociation of bound membrane bound organelle (MBO) cargoes. Cyclin-dependent kinase 5 (Cdk5) and protein phosphatase 1 (PP1) indirectly promote MBO cargo dissociation through mechanisms involving GSK3 activation. (B) Similarly, some kinases promote reductions in cytoplasmic dynein (cDyn)-mediated retrograde FAT; however, the precise mechanisms mediating their effects remain unclear. Interestingly, protein kinase C delta (PKCδ) increases retrograde FAT; but again, the underlying mechanisms are unknown. In the context of Alzheimer’s disease and other neurodegenerative diseases, these observations provide a molecular link between abnormal kinase/phosphatase signaling, deficits in FAT, and dying-back degeneration of neurons. Green arrows indicate movement of motor complexes; an “X” indicates inhibition of this movement; the larger green arrow indicates enhanced movement.

Fig. 2

Signaling pathways linking alterations in phosphotransferases to axonal transport defects, axonal degeneration, and cell death in AD. (A) A general schematic for the proposed role of phosphotransferases and axonal dysfunction in the pathogenesis of numerous neurodegenerative diseases characterized by a dying-back pattern of degeneration. (B) Plugging Alzheimer’s disease (AD)-specific pathologies into the schematic clearly suggests that there are many parallel and potentially interacting pathways that begin with abnormalities in known disease-associated factors (i.e. abnormal tau protein, mutant PS1, amyloid-β oligomers), and through aberrant activation of kinase and/or phosphatases, lead to impaired axonal transport, neuroanatomical disconnection of disease-related brain structures, functional deficits and eventually neurodegeneration (later in disease). Indeed, relatively subtle abnormalities in fast axonal transport, synaptic function and connectivity among neurons likely underlie the initial clinical symptoms of AD and as the disease progresses these pathways are further activated ultimately causing neurodegeneration and further functional impairment. Dashed arrows indicate secondary interconnections among toxic pathways that might contribute to pathological progression; green arrows indicate facilitating mechanisms, blunt-ended arrows indicate inhibitory mechanisms.