The Failure in NGF Maturation and its Increased Degradation as the Probable Cause for the Vulnerability of Cholinergic Neurons in Alzheimer’s Disease
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- Cuello, A.C. & Bruno, M.A. Neurochem Res (2007) 32: 1041. doi:10.1007/s11064-006-9270-0
This short review discusses the arguments to consider the dismetabolism of the pathway responsible for both the maturation and degradation of NGF as the culprit of vulnerability of the forebrain cholinergic system to the Alzheimer’s disease neuropathology. This summary includes information regarding a novel metabolic cascade converting Pro-NGF to mature NGF in the extracellular space and its ultimate degradation by a metalloprotease. It also describes how this pathway is altered in Alzheimer’s disease with the consequential CNS accumulation of proNGF and impairment in the formation of NGF along with increased degradation of this key trophic factor. This metabolic scenario in Alzheimer’s disease should result in the failure of NGF trophic support to forebrain cholinergic neurons and thus explaining the vulnerability of these neurons in this neurodegenerative condition.
KeywordsAlzheimer’s diseasePro-NGFNGFMetalloproteaseCholinergic neuronsTrophic factorNeurodegeneration
It is for these authors a great privilege to contribute to a tribute to Moussa Youdim who has been one of the most influential pharmacologists in the search for novel therapeutics to revert the degenerative process of dopaminergic neurons in Parkinson disease. For one of us (A. Claudio Cuello), this is particularly so because their paths have crossed in Oxford and McGill at different times, and because they share strong scientific interests and a long friendship; and for the co-author (Martin A. Bruno), it is a privilege because he has benefited from Moussa’s inspirational lectures at McGill. Moussa’s broad interests include the cholinergic system and Alzheimer’s disease. The cholinergic involvement in Alzheimer’s disease (AD) pathology is well established and need not be fully reviewed here. It may suffice to say that several decades ago, a significant loss of neurochemical cholinergic markers in the cerebral cortex of AD brains was reported by Davis and collaborators, and Bowen and collaborators [1, 2]. Further to this, Whitehouse et al.  reported the loss of cholinergic neurons presumptively in the nucleus magnocellularis of Meynert, i.e., nucleus basalis, in post-mortem samples of AD sufferers (no cholinergic markers were yet available). This prompted the formulation of the so-called “cholinergic hypothesis of AD”, with the knowledge of the central role of cholinergic neurons in memory mechanisms. The hypothesis was equivalent to the anterograde loss of dopaminergic neurons in Parkinson’s disease, assuming an anterograde loss of cholinergic neurons in AD. We instead proposed in 1984  that the cholinergic involvement in AD was secondary to cortical lesion (retrograde degeneration) based on our experimental evidence for basalis nucleus cell shrinkage following stroke-type cortical lesions . Since those early studies, we have learned a great deal about the relationship between the cortical amyloid burden and the cholinergic synaptic involvement thanks to the development of transgenic animal models of the AD-like amyloid pathology. Thus, we have been able to establish a pathology and time-dependent involvement of cortical cholinergic synaptic losses and generation of cholinergic dystrophic neurites in such models . In brief, these investigations clearly signal the preferential vulnerability of cortical terminations of cholinergic projections of the basal forebrain in the presence of progressive Aβ-induced pathology, a finding which is consistent with the abundant literature from neurochemical studies in AD human brain material. What is important, however, from the transgenic studies is that the Aβ burden per se, without any added factor (e.g., tau pathology), is sufficient to replicate the vulnerability of cortical cholinergic projections observed in the AD brain.
Forebrain cholinergic neurons, as is well established, are highly dependent of the endogenous supply of NGF throughout life. This concept could be extended to the day to day supply of NGF in the cerebral cortex. This is illustrated in experiments in which blocking endogenous NGF in the cerebral cortex with monoclonal antibodies or TrkA antagonist results in the rapid disappearance of pre-existing cholinergic synapses . Would a failure in NGF supply in AD therefore explain the remarkable vulnerability of the NGF-dependent forebrain cholinergic neurons? This issue was investigated early by many authors who found no evidence for such a deficiency. In most cases, the AD brain revealed normal or augmented NGF mRNA [8, 9] and normal or augmented NGF [10–12]. More recently, the work of Fahnestock and collaborators  clearly indicates that in AD there is an unequivocal up-regulation of the NGF precursor molecule, proNGF. Moreover, it has been proposed that, in the adult CNS, proNGF expression is up-regulated following CNS lesions, probably contributing to cell death through p75NTR and sortilin [14, 15].
For over two decades, it has been assumed that the mature NGF form accounts for the neurotrophin’s biological activity, including cell survival, neurite outgrowth and neuronal differentiation. The realization that proNGF might play a biological role in the CNS raised questions regarding the regulatory mechanisms leading to its release, as well as the control of the proNGF to NGF ratio and ultimately the degradation of the NGF molecule. To answer these questions, we embarked on a series of in vitro and in vivo studies aimed at elucidating the preferential NGF form released from the cerebral cortex and the pathway leading to NGF maturation and degradation. These studies have revealed that proNGF is the main releasable form of the neurotrophin and that the maturation and degradation of NGF largely occurs in the extracellular space with the involvement of a complex protease cascade .
(A) Human middle frontal gyrus samples (B) Relative protein levels in AD versus control samples
F and M
F and M
Alzheimer’s versus control
In conclusion, we are proposing that the well established vulnerability of NGF-dependent forebrain cholinergic neurons in AD is caused by a profound dismetabolism of the complex protease cascade which is responsible of the maturation and degradation of NGF in the extracellular space. Both animal and human brain data support this hypothesis. We further proposed that the accumulation of Aβ peptides provokes this metabolic dysregulation via mechanisms under investigation. Finally, such a situation would create a “feed-forward” pathological cycle in which the progressive accumulation of Aβ will disregulate the NGF metabolic cascade provoking cholinergic atrophy, which, in its turn, will favor an amyloidogenic metabolism of APP escalating the NGF compromise.
This work was supported by a grant from the Canadian Institutes of Health Research (MOP 62735) and a grant from the US Alzheimer’s Association (IIRG-06-25861). Dr. Claudio Cuello holds a Charles E. Frosst Merck Research Chair in Pharmacology at McGill University.