Elsevier

Experimental Neurology

Volume 246, August 2013, Pages 44-53
Experimental Neurology

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

https://doi.org/10.1016/j.expneurol.2012.06.003Get rights and content

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.

Introduction

Alzheimer's disease (AD) is a neurodegenerative disease representing the most prevalent form of dementia worldwide. The vast majority of AD patients have the sporadic, late-onset form of the disease (sAD). The gradual loss of cognitive function that characterizes AD involves progressive dysfunction and degeneration of specific neuronal populations within the central nervous system (Holtzman et al., 2011). The major histopathological hallmarks of AD include extracellular plaques composed of amyloid-β (Aβ) peptides and intracellular fibrillar tau aggregates known as neurofibrillary tangles (NFTs) (Holtzman et al., 2011). Rare, familial forms of AD (fAD) are caused by mutations in amyloid precursor protein (APP) and presenilins 1 and 2 (PS1, PS2) (Bekris et al., 2010), polypeptides functionally related to Aβ production (O'Brien and Wong, 2011). In addition, the identification of tau mutations as causative of various human disorders (collectively termed tauopathies) has directly linked abnormalities in tau to neurodegeneration (Goedert and Jakes, 2005). Similar clinical characteristics between fAD and sAD suggested the existence of common pathogenic mechanisms (Bossy-Wetzel et al., 2004) fueling the development of animal AD models based on expression of fAD-related mutant polypeptides (Ashe and Zahs, 2010). Although molecular pathways linking fAD-associated forms of APP and PS, as well as mutant tau to neurodegeneration are not fully elucidated, an analysis of the early pathogenic events in these animal models and in brains of sAD patients reveals potential mechanisms.

Section snippets

Neurons affected in AD follow a “dying-back” pattern of degeneration

Synaptic dysfunction during early sAD stages is thought to underlie the memory and cognitive deficits characteristic of this disease (Bell and Claudio Cuello, 2006). Accordingly, neuronal populations affected in AD feature abnormalities in synapse morphology and marked reductions in the total number of synapses (DeKosky and Scheff, 1990, Masliah et al., 1991a, Masliah et al., 1991b). Moreover, Aβ peptides reportedly inhibit synaptic function in a variety of experimental systems [reviewed in (

Axonal transport: a critical cellular process underlying axonal and synaptic function

The ubiquitous tissue expression of fAD-associated gene products contrasts sharply with the selective vulnerability of neurons observed in AD suggesting that one or more cellular features render neuronal cells increasingly vulnerable. Unlike any other cell type, neurons feature unusually long dendrites and axons, cytoplasmic projections that facilitate the reception, processing and transmission of chemical information via synaptic contacts with other neurons. Axonal length varies from the

Axonal transport defects in AD

Recently, the term “dysferopathy” (from the Greek word “fero”: to carry, transport) was coined by our group to describe neurodegenerative diseases featuring alterations in FAT and dying-back degeneration of neurons (Morfini et al., 2007b, Morfini et al., 2009a). Significantly, a large body of evidence demonstrated alterations in FAT in animal models of AD and tauopathies (Gotz et al., 2006), prompting us to posit that AD could be described, at least in part, as a dysferopathy (Morfini et al.,

Phosphotransferases regulate fast axonal transport

Basic neuronal functions depend upon the exquisitely regulated delivery of specific MBOs to numerous specialized axonal compartments. For example, saltatory conduction relies on the localized delivery of MBOs containing sodium channels at the nodes of Ranvier. Similarly, effective neurotransmission requires the sustained supply of synaptic vesicle precursors to hundreds of “en passant” and terminal synapses in CNS neurons (Morfini et al., 2001b). The required specificity of local cargo delivery

Misregulation of phosphotransferase-based pathways in AD

Mechanisms underlying FAT impairments in sAD are not well understood and multiple possibilities exist (see above and Table 1). However, experimental evidence from various fAD animal models illuminated specific kinase-based pathways linking fAD-related proteins to alterations in FAT. In AD, aberrant patterns of protein phosphorylation and misregulation of phosphotransferase activities have long been recognized. Moreover, the presence of abnormally phosphorylated proteins (e.g. tau) represents a

Phosphotransferases and pathogenic proteins: which are viable therapeutic targets?

The most important insight that can be gleaned from the strong link between misregulation of phosphotransferases, FAT deficits and synaptic degeneration in AD is the identification of potential therapeutic targets. In this regard, the observations discussed here provide a conceptual framework for devising novel therapeutic treatments in AD. If the FAT deficits that characterize this disease indeed result from alterations in the activity of phosphotransferases, these could be corrected using

Conclusions

Studies continue to demonstrate a strong link between phosphotransferase misregulation, FAT deficits and neurodegeneration in AD, as well as other neurodegenerative diseases. The unique burden of maintaining FAT and well-orchestrated delivery of specific cargoes to select subdomains of neurons makes them particularly susceptible to perturbations in FAT. This notion supports the long recognized, yet unexplained, fact that adult-onset neurodegenerative diseases typically feature increased

Acknowledgments

This paper is dedicated to the loving memory of Mario Felipe Morfini (GM). This work was supported by NIH T32 AG020506-07 and Alzheimer's Association NIRG-10-174461 (NMK); NIH NS23868 (STB); NIH AG09466 (LIB); Alzheimer's Association NIRGD-11-206379 (to GP); Brain Research Foundation grants (OL and GM); NIH/NIA AG033570 and NIA 1RC1AG036208-01 ARRA (OL); and NIH NS066942A and ALS/CVS Therapy Alliance grants (GM).

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