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NGF and the Amyloid Precursor Protein in Alzheimer’s Disease: From Molecular Players to Neuronal Circuits

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Recent Advances in NGF and Related Molecules

Part of the book series: Advances in Experimental Medicine and Biology ((CNNCSN,volume 1331))

Abstract

Alzheimer’s disease (AD), one of the most common causes of dementia in elderly people, is characterized by progressive impairment in cognitive function, early degeneration of basal forebrain cholinergic neurons (BFCNs), abnormal metabolism of the amyloid precursor protein (APP), amyloid beta-peptide (Aβ) depositions, and neurofibrillary tangles. According to the cholinergic hypothesis, dysfunction of acetylcholine-containing neurons in the basal forebrain contributes markedly to the cognitive decline observed in AD. In addition, the neurotrophic factor hypothesis posits that the loss nerve growth factor (NGF) signalling in AD may account for the vulnerability to atrophy of BFCNs and consequent impairment of cholinergic functions. Though acetylcholinesterase inhibitors provide only partial and symptomatic relief to AD patients, emerging data from in vivo magnetic resonance imaging (MRI) and positron emission tomography (PET) studies in mild cognitive impairment (MCI) and AD patients highlight the early involvement of BFCNs in MCI and the early phase of AD. These data support the cholinergic and neurotrophic hypotheses of AD and suggest new targets for AD therapy.

Different mechanisms account for selective vulnerability of BFCNs to AD pathology, with regard to altered metabolism of APP and tau. In this review, we provide a general overview of the current knowledge of NGF and APP interplay, focusing on the role of APP in regulating NGF receptors trafficking/signalling and on the involvement of NGF in modulating phosphorylation of APP, which in turn controls APP intracellular trafficking and processing. Moreover, we highlight the consequences of APP interaction with p75NTR and TrkA receptor, which share the same binding site within the APP juxta-membrane domain. We underline the importance of insulin dysmetabolism in AD pathology, in the light of our recent data showing that overlapping intracellular signalling pathways stimulated by NGF or insulin can be compensatory. In particular, NGF-based signalling is able to ameliorates deficiencies in insulin signalling in the medial septum of 3×Tg-AD mice. Finally, we present an overview of NGF-regulated microRNAs (miRNAs). These small non-coding RNAs are involved in post-transcriptional regulation of gene expression, and we focus on a subset that are specifically deregulated in AD and thus potentially contribute to its pathology.

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Acknowledgements

This work was supported by Finanziamento delle Attività Base di Ricerca FFABR to NC. Graphic elaboration of the illustration by VT was partially realized with vectorial images from ‘FreeVector.com’, under Creative Common Attribution 4.0 International (CC BY 4.0). A special thanks to Dr. V. Sposato for her contribution to the experimental work.

The authors apologize for the scientific publications not acknowledged in this manuscript because of space restrictions.

The authors sincerely apologize to all those colleagues whose important work was not cited in this paper owing to space limitations.

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Authors and Affiliations

  1. Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Campus A. Buzzati-Traverso, Monterotondo, RM, Italy

    Viviana Triaca, Francesca Ruberti & Nadia Canu

  2. Department of System Medicine, Section of Physiology, University of Rome “Tor Vergata”, Rome, Italy

    Nadia Canu

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  1. Viviana Triaca
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  2. Francesca Ruberti
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  3. Nadia Canu
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Correspondence to Nadia Canu .

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  1. University of Bologna, Ozzano dell’Emilia, Bologna, Italy

    Laura Calzà

  2. IRET Foundation, Ozzano dell’Emilia, Bologna, Italy

    Luigi Aloe

  3. University of Bologna, Ozzano dell’Emilia, Bologna, Italy

    Luciana Giardino

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Triaca, V., Ruberti, F., Canu, N. (2021). NGF and the Amyloid Precursor Protein in Alzheimer’s Disease: From Molecular Players to Neuronal Circuits. In: Calzà, L., Aloe, L., Giardino, L. (eds) Recent Advances in NGF and Related Molecules. Advances in Experimental Medicine and Biology(), vol 1331. Springer, Cham. https://doi.org/10.1007/978-3-030-74046-7_10

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