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Review
. 2025 May 21;26(10):4926.
doi: 10.3390/ijms26104926.

BDNF/proBDNF Interplay in the Mediation of Neuronal Apoptotic Mechanisms in Neurodegenerative Diseases

Marina Mitrovic  1 , Dragica Selakovic  2 , Nemanja Jovicic  3 , Biljana Ljujic  4 , Gvozden Rosic  2
Affiliations
Review

BDNF/proBDNF Interplay in the Mediation of Neuronal Apoptotic Mechanisms in Neurodegenerative Diseases

Marina Mitrovic et al. Int J Mol Sci. .

Abstract

The neurotrophic system includes neurotrophins, such as brain-derived neurotrophic factor (BDNF) and its precursor proBDNF, which play conflicting roles in neuronal survival and apoptosis, with their balance having a significant impact on neurodegenerative outcomes. While BDNF is widely acknowledged as a potent neurotrophin that promotes neuronal survival and differentiation, its precursor, proBDNF, has the opposite effect, promoting apoptosis and neuronal death. This review highlights the new and unique aspects of BDNF/proBDNF interaction in the modulation of neuronal apoptotic pathways in neurodegenerative disorders. It systematically discusses the cross-talk in apoptotic signaling at the molecular level, whereby BDNF activates survival pathways such as PI3K/Akt and MAPK/ERK, whereas proBDNF activates p75NTR and sortilin to induce neuronal apoptosis via JNK, RhoA, NFkB, and Rac-GTPase pathways such as caspase activation and mitochondrial injury. Moreover, this review emphasizes the factors that affect the balance between proBDNF and BDNF levels within the context of neurodegeneration, including proteolytic processing, the expression of TrkB and p75NTR receptors, and extrinsic gene transcription regulators. Cellular injury, stress, or signaling pathway alterations can disrupt the balance of BDNF/proBDNF, which may be involved in apoptotic-related neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington's diseases. This review provides a comprehensive framework for targeting neurotrophin signaling in the development of innovative therapies for neuronal survival and managing apoptotic-related neurodegenerative disorders, addressing the mechanistic complexity and clinical feasibility of BDNF/proBDNF interaction.

Keywords: Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; apoptosis; neurotrophin receptors; neurotrophins.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
BDNF and proBDNF pathways in apoptotic signaling regulation.
Figure 2
Figure 2
BDNF/TrkB activation and signaling pathways.
Figure 3
Figure 3
Current therapeutic strategies targeting BDNF and proBDNF signaling scheme.
See this image and copyright information in PMC

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