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The human brain NGF metabolic pathway is impaired in the pre-clinical and clinical continuum of Alzheimers disease

Abstract

The NGF metabolic pathway entails the proteins that mature pro-nerve growth factor (proNGF) to NGF and those that degrade NGF. Basal forebrain cholinergic neurons require NGF for maintenance of cholinergic phenotype, are critical for cognition, and degenerate early in Alzheimer’s disease (AD). In AD, NGF metabolism is altered, but it is not known whether this is an early phenomenon, nor how it relates to AD pathology and symptomology. We acquired dorsolateral/medial prefrontal cortex samples from individuals with Alzheimer’s dementia, Mild Cognitive Impairment (MCI), or no cognitive impairment with high (HA-NCI) and low (LA-NCI) brain Aβ from the Religious Orders Study. Cortical proNGF protein, but not mRNA, was higher in AD, MCI, and HA-NCI, while mature NGF was lower. Plasminogen protein was higher in MCI and AD brain tissue, with plasminogen mRNA not likewise elevated, suggesting diminished activation of the proNGF convertase, plasmin. The plasminogen activator tPA was lower in HA-NCI while neuroserpin, the CNS tPA inhibitor, was higher in AD and MCI cortical samples. Matrix metalloproteinase 9 (MMP9), which degrades NGF, was overactive in MCI and AD. Transcription of the MMP9 inhibitor TIMP1 was lower in HA-NCI. ProNGF levels correlated with plasminogen, neuroserpin, and VAChT while NGF correlated with MMP9 activity. In NCI, proNGF correlated with cerebral Aβ and tau deposition and to cognitive performance. In summary, proNGF maturation is impaired in preclinical and clinical AD while mature NGF degradation is enhanced. These differences correlate with cognition, pathology, and cholinergic tone, and may suggest novel biomarkers and therapeutic targets.

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Fig. 1: Schematic representation of the NGF metabolic pathway and its compromise in the continuum of Alzheimer’s disease.
Fig. 2: Normal NGF synthesis in the continuum of AD pathology is accompanied by an increase of proNGF and decrease of mNGF, beginning at preclinical stages, as well as abnormal expression of proteins participating in proNGF maturation.
Fig. 3: Increased levels and protease activity of MMP9, a mature-NGF degrading protease, and diminished expression of its endogenous inhibitor, TIMP1, at AD clinical stages in dorsolateral/medial prefrontal cortex homogenates.
Fig. 4: Association between elevations of dorsolateral/medial prefrontal cortex proNGF protein levels and hallmarks of Alzheimer’s neuropathology and to cognitive scores in individuals with no cognitive impairment (n= 59).
Fig. 5: VAChT expression across the AD continuum and its association with proNGF and neuroserpin expression.

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Acknowledgements

The authors express gratitude to the participants in the ROS study as well as to the team at the RUSH Medical Center for performing the cognitive testing and neuropathological analyses. The authors thank Dr. Daniel Lawrence from the Michigan Center for Integrative Research in Critical Care, USA for graciously providing the anti-neuroserpin antibody used in this study. The authors are also grateful for the revisions and suggestions provided by Drs Ezio Giacobini, Harald Hampel, and Giancarlo Pepeu on this manuscript. ACC acknowledges financial support from the Canadian Institutes of Health Research (CIHR) and the Alzheimer Society of Canada. He holds the McGill University Charles E. Frosst/Merck Chair in Pharmacology and is a member of the Canadian Consortium of Neurodegeneration in Aging. ACC wishes to thank Merck Canada for their unrestricted support. DAB was supported by grants P30AG10161 and R01AG15819 from the NIA. RP was the recipient of a Student Fellowship from the McGill Integrated Program in Neuroscience and CIHR Doctoral Award. MFI acknowledges support from a Bourse Postdoctorale from the Fonds de Recherche du Quebec Santé (FRQS). The funding bodies had no role in the design of the study or in the collection, analysis, and interpretation of data or in writing the manuscript.

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RP, MFI, and ACC conceived and designed the study. RP measured the proteins and transcripts in brain with guidance from MFI, AD, and ACC. DAB provided brain tissue as well as neuropathological and cognitive data. RP generated and analyzed the data. RP, MFI, and ACC wrote the manuscript. All authors have read and revised the final version of the manuscript.

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Correspondence to A. Claudio Cuello.

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Pentz, R., Iulita, M.F., Ducatenzeiler, A. et al. The human brain NGF metabolic pathway is impaired in the pre-clinical and clinical continuum of Alzheimers disease. Mol Psychiatry 26, 6023–6037 (2021). https://doi.org/10.1038/s41380-020-0797-2

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