ngf and alzheimer's disease: unfulfilled promise and untapped potential

2
Neurobiology of Aging. Vol. 10, pp. 543-544. ©Pergamon Press plc, 1989. Printed in the U.S.A. 0197-4580/89 $3.00 + .00 NGF and Alzheimer's Disease: Unfulfilled Promise and Untapped Potential JEFFREY H. KORDOWER* AND ELLIOTT J. MUFSON? *Department of Anatomy and Cell Biology, University of Illinois School of Medicine, 808 S. Wood Street Chicago, IL 60612 ~'Christopher Center for Parkinson's Research, Institute for Biogerontology Research, Sun City, AZ 85351 A role for impaired NGF mechanisms as an underlying component in the pathogenesis of Alzheimer's disease has yet to be realized. However, circumspect examination of the available data fails to provide sufficient evidence for rejecting this notion and further systematic evaluation along each step of NGF's mechanism of neurotrophic action is still required. This commentary argues that NGF may be involved in the degeneration observed in the basal forebrain in AD, or at the very least, plays a dynamic role in the disease process. HEFTI and colleagues have assimilated a vast amount of literature dealing with the blossoming field of neuronotropic substances, a topic of great interest to both basic and clinical scientists. Their review concentrates to a large extent on the involvement of the prototype trophic substance nerve growth factor (NGF), as a paradigmatic model for the study of trophic molecules in devel- opment, trophic responses to brain injury, and as a possible pharmacologic therapeutic agent for the treatment of neurodegen- erative disease. Dr. Hefti and his co-workers' have succeeded in presenting a scholarly and timely review of a domain for which they have contributed enumerable seminal findings. Taking ad- vantage of the open peer commentary format, we wish to elaborate on select key issues addressed in this review. Hefti and co-workers (6,7) initial hypothesis suggesting that alterations in NGF mechanisms may underlie certain aspects of the pathogenesis in Alzheimer's disease (AD) served to focus atten- tion on this important question and resulted in concentrated efforts examining the relationships between NGF and AD. What is currently known about both NGF and AD, however, would suggest a redefining of the limits of the initial hypothesis. It can be stated with some certainty that NGF is not involved in the widespread neuropathology seen in AD. Instead, NGF may underlie, in part, the neuronal degeneration observed within the cholinergic basal forebrain in AD. The initial promise for a positive resolution of even this more circumscribed postulate has not yet been realized and some have been tempted to quickly reject it. However, an evaluation of the available data suggests that it may be premature to abandon the concept that NGF is involved in the destruction of the cholinergic basal forebrain in diseases of dementia. It is true that the expression of the NGF message (4) and the presence of NGF receptors upon the residual cholinergic basal forebrain neurons (11) are reportedly unchanged in AD. However, for NGF to exert its trophic effects upon cholinergic basal forebrain neurons several factors have to be considered including: a) the expression of NGF mRNA; b) the proper translational steps must be carried out for the synthesis of the NGF protein; c) the NGF protein must be synthesized in sufficient quantities; d) available NGF must bind effectively to a sufficient number of NGF receptors (which itself has its complementary set of require- ments for synthesis); e) the NGF/NGF receptor interaction must be transduced and internalized and f) active retrograde transport of the molecule back to the cell soma must occur. Failure at any of these steps will likely prevent the neurotropic effects of NGF from taking place. Systematic comparisons between AD cases and age-matched controls have not been assessed for each of these steps. Indeed, some of these steps will be difficult to experimen- tally evaluate. Studies examining the relationships between NGF and AD have to be limited in their interpretation due to the widespread and heterogeneous pathology observed in postmortem AD cases. While the important study by Goedart and co-workers (4) indicates that levels of NGF mRNA are not reduced in AD, it is important to note that only one cortical area was assessed in only 5 AD patients. In fact, data from this study revealed a reduction of NGF mRNA of almost 30% that due to variability failed to reach statistical significance. Since the pathology in AD exhibits sub- stantial regional heterogeneity, it would be premature to accept that there are no differences in NGF mechanisms for even this single parameter. As acknowledged by these authors (4), larger scale studies are needed to fully assess the integrity of NGF mRNA in AD. We (11) have recently demonstrated that NGF receptors are present on basal forebrain neurons in AD and these cells demonstrate the same high degree of colocalization with choline acetyltransferase (CHAT) as age-matched controls. How- ever, this study examined only the presence or absence of NGF receptors and not their levels. Whether there are normal numbers of NGF receptors per basal forebrain neuron in AD, or at least levels sufficient to adequately transduce the NGF signal, also remains to be established. Dichotomies exist which provide further evidence that NGF trophic systems are in a dynamic state during the AD degenerative process. Postmortem AD cases reveal widespread pathology and significant loss of neurons within the pyramidal cell layer of the hippocampal formation [e.g., (1)]. There is also extensive degen- eration within the neocortex and entorhinal cortex in AD (8, 13, 17). Since neurons within the hippocampus (5) and probably the cortex as well, appear to synthesize NGF for retrograde transport to the septal/diagonal band (Chl and Ch2) region and nucleus basalis (Ch4), how can the levels of NGF mRNA and protein remain unchanged in AD following such extensive neuronal degeneration? One possibility is that there is an up-regulation of NGF production in the remaining cortical and hippocampal neu- rons spared by this disease. A second possibility includes the "'de novo" synthesis of NGF from either other neuronal cell types or nonneuronal elements. Such "de nov&' synthesis occurs in the peripheral nervous system from Schwann cells following transec- tion of peripheral nerves (5). While such synthesis has yet to be demonstrated in the central nervous system, damage to the adult rodent striatum (or infusion of NGF) can result in the new or unmasked synthesis of NGF receptors by cholinergic striatal neurons (2). NGF and its receptor have a well established positive

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Neurobiology of Aging. Vol. 10, pp. 543-544. © Pergamon Press plc, 1989. Printed in the U.S.A. 0197-4580/89 $3.00 + .00

NGF and Alzheimer's Disease: Unfulfilled Promise and Untapped Potential

J E F F R E Y H. K O R D O W E R * A N D E L L I O T T J. M U F S O N ?

*Department of Anatomy and Cell Biology, University of Illinois School of Medicine, 808 S. Wood Street Chicago, IL 60612

~'Christopher Center for Parkinson's Research, Institute for Biogerontology Research, Sun City, AZ 85351

A role for impaired NGF mechanisms as an underlying component in the pathogenesis of Alzheimer's disease has yet to be realized. However, circumspect examination of the available data fails to provide sufficient evidence for rejecting this notion and further systematic evaluation along each step of NGF's mechanism of neurotrophic action is still required. This commentary argues that NGF may be involved in the degeneration observed in the basal forebrain in AD, or at the very least, plays a dynamic role in the disease process.

HEFTI and colleagues have assimilated a vast amount of literature dealing with the blossoming field of neuronotropic substances, a topic of great interest to both basic and clinical scientists. Their review concentrates to a large extent on the involvement of the prototype trophic substance nerve growth factor (NGF), as a paradigmatic model for the study of trophic molecules in devel- opment, trophic responses to brain injury, and as a possible pharmacologic therapeutic agent for the treatment of neurodegen- erative disease. Dr. Hefti and his co-workers' have succeeded in presenting a scholarly and timely review of a domain for which they have contributed enumerable seminal findings. Taking ad- vantage of the open peer commentary format, we wish to elaborate on select key issues addressed in this review.

Hefti and co-workers (6,7) initial hypothesis suggesting that alterations in NGF mechanisms may underlie certain aspects of the pathogenesis in Alzheimer's disease (AD) served to focus atten- tion on this important question and resulted in concentrated efforts examining the relationships between NGF and AD. What is currently known about both NGF and AD, however, would suggest a redefining of the limits of the initial hypothesis. It can be stated with some certainty that NGF is not involved in the widespread neuropathology seen in AD. Instead, NGF may underlie, in part, the neuronal degeneration observed within the cholinergic basal forebrain in AD. The initial promise for a positive resolution of even this more circumscribed postulate has not yet been realized and some have been tempted to quickly reject it. However, an evaluation of the available data suggests that it may be premature to abandon the concept that NGF is involved in the destruction of the cholinergic basal forebrain in diseases of dementia. It is true that the expression of the NGF message (4) and the presence of NGF receptors upon the residual cholinergic basal forebrain neurons (11) are reportedly unchanged in AD. However, for NGF to exert its trophic effects upon cholinergic basal forebrain neurons several factors have to be considered including: a) the expression of NGF mRNA; b) the proper translational steps must be carried out for the synthesis of the NGF protein; c) the NGF protein must be synthesized in sufficient quantities; d) available NGF must bind effectively to a sufficient number of NGF receptors (which itself has its complementary set of require- ments for synthesis); e) the NGF/NGF receptor interaction must be transduced and internalized and f) active retrograde transport of the molecule back to the cell soma must occur. Failure at any of these steps will likely prevent the neurotropic effects of NGF from taking place. Systematic comparisons between AD cases and age-matched controls have not been assessed for each of these

steps. Indeed, some of these steps will be difficult to experimen- tally evaluate. Studies examining the relationships between NGF and AD have to be limited in their interpretation due to the widespread and heterogeneous pathology observed in postmortem AD cases. While the important study by Goedart and co-workers (4) indicates that levels of NGF mRNA are not reduced in AD, it is important to note that only one cortical area was assessed in only 5 AD patients. In fact, data from this study revealed a reduction of NGF mRNA of almost 30% that due to variability failed to reach statistical significance. Since the pathology in AD exhibits sub- stantial regional heterogeneity, it would be premature to accept that there are no differences in NGF mechanisms for even this single parameter. As acknowledged by these authors (4), larger scale studies are needed to fully assess the integrity of NGF mRNA in AD. We (11) have recently demonstrated that NGF receptors are present on basal forebrain neurons in AD and these cells demonstrate the same high degree of colocalization with choline acetyltransferase (CHAT) as age-matched controls. How- ever, this study examined only the presence or absence of NGF receptors and not their levels. Whether there are normal numbers of NGF receptors per basal forebrain neuron in AD, or at least levels sufficient to adequately transduce the NGF signal, also remains to be established.

Dichotomies exist which provide further evidence that NGF trophic systems are in a dynamic state during the AD degenerative process. Postmortem AD cases reveal widespread pathology and significant loss of neurons within the pyramidal cell layer of the hippocampal formation [e.g., (1)]. There is also extensive degen- eration within the neocortex and entorhinal cortex in AD (8, 13, 17). Since neurons within the hippocampus (5) and probably the cortex as well, appear to synthesize NGF for retrograde transport to the septal/diagonal band (Chl and Ch2) region and nucleus basalis (Ch4), how can the levels of NGF mRNA and protein remain unchanged in AD following such extensive neuronal degeneration? One possibility is that there is an up-regulation of NGF production in the remaining cortical and hippocampal neu- rons spared by this disease. A second possibility includes the "'de novo" synthesis of NGF from either other neuronal cell types or nonneuronal elements. Such "de nov&' synthesis occurs in the peripheral nervous system from Schwann cells following transec- tion of peripheral nerves (5). While such synthesis has yet to be demonstrated in the central nervous system, damage to the adult rodent striatum (or infusion of NGF) can result in the new or unmasked synthesis of NGF receptors by cholinergic striatal neurons (2). NGF and its receptor have a well established positive

544 KORDOWER AND MUFSON

feedback relationship in that high levels of NGF are reflected in high levels of its receptor and vice versa (5). It can be speculated that the reexpression of NGF receptors upon striatal interneurons is accompanied by increased levels of NGF protein in this region as well. The dichotomy between NGF mRNA levels and known neuronal pathology suggests that NGF mechanisms are playing an active role during the disease process. Indeed, a dynamic NGF- mediated trophic response may be engaged following neuronal degeneration and is responsible for the sprouting of new cholin- ergic terminals seen within the AD hippocampus (3).

When discussing levels of NGF in the adult mammalian brain, it is common to describe such levels as being highest within the hippocampus and cerebral cortex. However, a closer examination of the data reveals that cortex contains 40%-50% of the levels of [3NGF protein found within the hippocampus [e.g., (12,16)]. The amygdala, another locus receiving extensive cholinergic basal forebrain input, contains minimal amounts of NGF (5) and lacks NGF receptor-immunoreactive fibers (9,14). One would predict that if NGF mechanisms are involved in the pathogenesis of the cholinergic basal forebrain in AD, the amygdatoid components of this system would be most vulnerable. In contrast, hippocampal projecting neurons would be most protected under NGF's "trophic umbrella." We have recently found this to be the case (15). The anterolateral portion of the nucleus basalis (Ch4al), which carries the bulk of the cholinergic input to the amygdala in primates [e.g., (10)], displayed among the greatest (76.4%) loss of NGF receptor- containing neurons within the basal forebrain. In contrast, while some of the hippocampal projecting cholinergic neurons emanat- ing from the medial septal/vertical limb of the diagonal band region (Chl-Ch2) were atrophic, this region displayed only a small (16.7%) statistically nonsignificant dimunition in the hum-

ber of NGF receptor-containing neurons. Other regions of the basal forebrain, such as the anteromedial or intermediate portions of the nucleus basalis, displayed intermediate decreases in neuron number. Importantly, Nissl-counterstained sections and tissue sections which colocalized the NGF receptor and ChAT (11,15) failed to reveal viable magnocellular basal forebrain neurons which did not continue to express the NGF receptor. Thus reductions in NGF receptor-containing neurons reflected a true loss of neurons and not the failure of viable neurons to synthesize the NGF receptor. We do not interpret this data as being direct and complete evidence for a role of NGF in the pathogenesis of the cholinergic basal forebrain. Rather, it serves to highlight the fact that our knowledge of the role NGF plays in aging and diseases of cognition is incomplete and further examination is needed before definitive conclusions can be made concerning the role of NGF in AD.

To summarize, there is no direct evidence as of yet to suggest that impaired NGF mechanisms are responsible for the degenera- tion seen within the basal forebrain in AD. The mechanisms of action for NGF, however, have not been fully elucidated nor is there a clear understanding of the pathogenesis of AD. Therefore, this hypothesis deserves a closer and more systematic evaluation before being rejected. Whether or not impaired NGF mechanisms are involved in basal forebrain degeneration is a separate issue from whether NGF therapy will be of clinical value for AD patients. NGF therapy may provide some benefit to AD sufferers although its utility would appear to be limited by the lack of early diagnostic markers for this disease. However, given the indisput- able course this insidious disease will take, even the potential for modest benefit may warrant its clinical evaluation.

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