Full-length reviewNeurotrophic factors in Alzheimer’s and Parkinson’s disease brain
Introduction
Neurotrophic factors (NTFs) are secreted peptides that act as growth factors for the phenotypic development and maintenance of specific neuronal populations in developing and adult vertebrate nervous system. These diffusible proteins that act via retrograde signaling from target-neurons and by paracrine and autocrine mechanisms regulate many aspects of neuronal and glial structure and function [242].
Neurotrophic factors promote neuronal survival, stimulate axonal growth and influence axonal target finding to establish synaptic contacts during development. It has been proposed that growing axons compete for limited amounts of neurotrophic factors, which are produced by target tissues [85], [241]. Neurons which fail to obtain a sufficient quantity of the necessary neurotrophic factors die by a process called programmed cell-death [45], [207]. Further, in adulthood, neurotrophic factors are required to maintain neuronal functions and specific neuronal phenotype [29]; however, it is unclear as to what degree the mature neurons remain dependent upon target-derived support. Newer evidence indicates that certain of the factors also are subject to anterograde transport to postsynaptic neurons and possibly to glia [12], [155] (Table 1). Neurotrophic factors not only promote the differentiation and growth of developing neurons and phenotypic maintenance and survival of adult mature neurons but also represent a potential means of modifying neuronal dysfunction, astrocytic activation and inflammatory reactions under pathological conditions. A large body of evidence suggests that some neurotrophic factors under certain conditions also modulate neuronal plasticity that emerges during aging and under traumatic or degenerative condition [29].
Thus, the importance of neurotrophic factors in the survival and phenotypic differentiation of developing neurons as well as maintenance and protection of mature and injured neurons in vertebrate nervous system is well documented [45], [58]. Recent evidence suggests that alterations in the neurotrophic levels either due to age, genetic background or other factors might contribute to neurodegeneration. It has been proposed that the loss of endogenous target-derived trophic support for selective neuronal populations may lead to the neuronal degeneration characteristic of Alzheimer’s, Parkinson’s and other neurodegenerative diseases but direct support for this hypothesis is currently lacking [45]. These concepts stress the importance of examining changing patterns of polypeptide and mRNA profiles of different neurotrophic factors and their receptor components under normal and pathological conditions. In the neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, it is possible that changes in the regulation of specific neurotrophic factors or their receptors are critical in the pathway of neuronal degeneration. These factors may be regulated differently in neurons and glia and in different neuronal subsets. Also, the factors may be subject to changes in local synthesis or in transport to or from target tissues (Table 1). Thus, in situ cell-specific data from both the regions of degeneration and of target neurons in human brain are needed to generate testable hypotheses for unique NTF roles in these diseases. The matter is made more complicated by the emerging evidence for cross-talk among the different families of NTFs [107].
Although there is ample evidence demonstrating the ameliorative effects of different recombinant neurotrophic factors and genetically engineered cells secreting neurotrophic factors in different animal and in vitro models of human neurodegenerative processes [34], very little is known about the actual distribution and regulation of neurotrophic factors in normal and diseased human brain per se [45]. This paper reviews all the available data regarding the distribution of neurotrophic factors and their receptors in human brain of Alzheimer’s and Parkinson’s diseases and in normal young and aged human nervous system from 1997 to April, 2000 by searching PubMed. Earlier reports have been extensively reviewed elsewhere [53], [98], [135], [189]. In addition, recent updates on neurotrophic receptor signaling in animal tissues are presented since this is an emerging subject pertinent to future studies in human brain. Certain work on non-human models is cited only where no comparable information is available for human brain. The interested reader will find many discussions of the general biology of neurotrophic factors [53], [98], [135], [155], [189], [194], [198], [242]. The purpose of the current review is to stimulate clinical research in order to exploit neurotrophins as potential therapeutic molecules in treating human neurodegenerative disorders [50], [227], [136], [155], [242] and in developing effective means for delivering these molecules into the brain [89], [233], [237].
Section snippets
Families of neurotrophic factors and their regulation
Most neurotrophic factors (NTFs) belong to several families of structurally and functionally related molecules: (1) nerve growth factor (NGF)-superfamily; (2) glial cell line-derived neurotrophic factor (GDNF) family; (3) neurokine or neuropoietin superfamily; (4) non-neuronal growth factor-superfamily. All these NTFs signal via specific multicomponent receptor complexes. NGF-superfamily receptors include p75 and the receptor protein tyrosine kinases (Trk), TrkA, TrkB and TrkC. GDNF family
Models of Alzheimer’s disease
Alzheimer’s disease (AD) is characterized by a progressive decline in cognitive function that correlates with a number of pathological changes in several different brain regions, one of the most prominent among the regions being the basal forebrain cholinergic neurons (BFCN). Therefore, most efforts in utilizing neurotrophic factors for therapy in AD research to date have focused on augmenting cholinergic functions [233]. The most commonly used experimental models of AD are: (1) lesioning of
Models of Parkinson’s disease
Parkinson’s disease is characterized by the selective degeneration of nigral dopaminergic neurons and subsequent depletion of striatal dopamine which leads to motor dysfunction. Therefore, the most popularly used experimental models of PD have been MPTP-and 6-OHDA-experimental lesions, which selectively result in nigral dopaminergic neuronal degeneration. These studies and evidence for the role of neurotrophic factors in the pathogenesis and potential treatment of Parkinson’s disease have been
Aging
The only available data found regarding changes in expression of any of the NTFs or their receptors during aging in human brain concern the receptor for fibroblastic growth factor, the p75 low affinity receptor for NGF and one report on the NGF superfamily [181]. As mentioned earlier, immunoreactive FGFR-1 declines in SN with age in human brain [226]. In nucleus basalis of Meynert, Salehi et al. [188] observed no relationship between age or sex and the expression of p75 in cell bodies but did
NGF-superfamily receptors
The neurotrophin family of ligands, consisting of NGF, BDNF, NT-3 and NT-4/5, associate as non-covalent homodimers in their biologically active form. Responsiveness of neurons to these factors depends on expression of two classes of cell surface receptors. One class is the 75 kDa transmembrane protein p75. The second class consists of three different receptor protein tyrosine kinases (RPTK), TrkA, TrkB and TrkC (Fig. 1). NGF has the highest affinity for TrkA, BDNF for TrkB, and NT-3 for TrkC.
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