Brain Derived Neurotrophic Factor (Bdnf) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes. [1]
Brain-Derived Neurotrophic Factor (BDNF) is a member of the neurotrophin family of growth factors that plays essential roles in neuronal survival, differentiation, synaptic plasticity, and cognitive function. BDNF is the most abundant neurotrophin in the adult brain, with particularly high expression in the [hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus--TEMP--/brain-regions)--FIX--, [cerebral [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX--, and [basal ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia--TEMP--/brain-regions)--FIX-- 1(https://pmc.ncbi.nlm.nih.gov/articles/PMC9138678/). In the context of [neurodegenerative diseases[/[diseases[/[diseases[/[diseases[/[diseases[/[diseases[/[diseases[/diseases, BDNF has emerged as a central mediator linking synaptic dysfunction, neuronal loss, and cognitive decline. [2]
Reduced BDNF expression has been consistently documented in [Alzheimer's disease[/diseases/[alzheimers[/diseases/[alzheimers[/diseases/[alzheimers--TEMP--/diseases)--FIX--, [Parkinson's disease[/diseases/[parkinsons[/diseases/[parkinsons[/diseases/[parkinsons--TEMP--/diseases)--FIX--, [Huntington's disease[/mechanisms/[huntington-pathway[/mechanisms/[huntington-pathway[/mechanisms/[huntington-pathway--TEMP--/mechanisms)--FIX--, and [ALS[/diseases/[als[/diseases/[als[/diseases/[als--TEMP--/diseases)--FIX--, making it both a promising biomarker and a therapeutic target for neurodegenerative conditions 2(https://www.mdpi.com/1422-0067/26/9/4271). The dual signaling system of mature BDNF (via TrkB receptors promoting survival) and proBDNF (via p75NTR promoting [apoptosis) provides a nuanced framework for understanding how neurotrophic signaling goes awry in neurodegeneration.
The human BDNF gene is located on chromosome 11p14.1 and has a complex structure with multiple promoters and at least nine 5' non-coding exons, each spliced to a common 3' coding exon. This architecture allows tissue-specific and activity-dependent regulation of BDNF expression 3(](https://link.springer.com/article/10.1007/s10571-017-0510-4).
BDNF is initially synthesized as a precursor protein (preproBDNF, ~32 kDa), which is cleaved to proBDNF (~28 kDa) in the endoplasmic reticulum. ProBDNF can be further processed to mature BDNF (~14 kDa) by intracellular furin or proprotein convertases, or extracellularly by plasmin and matrix metalloproteinases. Critically, proBDNF and mature BDNF have distinct and often opposing biological activities 4(https://www.mdpi.com/1422-0067/26/10/4926):
This yin-yang relationship between mBDNF and proBDNF is central to understanding BDNF's role in both normal brain function and neurodegeneration.
Mature BDNF binds with high affinity to the tropomyosin receptor kinase B (TrkB, also known as NTRK2), triggering receptor homodimerization and autophosphorylation of intracellular tyrosine residues. This activates three major downstream signaling cascades 3(https://link.springer.com/article/10.1007/s10571-017-0510-4):
ProBDNF preferentially binds to the p75 neurotrophin receptor (p75NTR), often in complex with the co-receptor sortilin. This activates 4(https://www.mdpi.com/1422-0067/26/10/4926) 5(https://www.nature.com/articles/srep03185):
The balance between TrkB and p75NTR signaling is critical: in neurodegeneration, reduced mBDNF levels and increased proBDNF may shift this balance toward pro-apoptotic signaling.
The Val66Met single nucleotide polymorphism (rs6265) in the BDNF gene is the most extensively studied genetic variant, present in approximately 20-30% of the population (higher frequency in Asian populations). The methionine substitution at codon 66 in the prodomain 6(https://content.iospress.com/articles/brain-plasticity/bpl210132):
BDNF is profoundly reduced in [Alzheimer's disease[/diseases/[alzheimers[/diseases/[alzheimers[/diseases/[alzheimers--TEMP--/diseases)--FIX--, particularly in the [hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus--TEMP--/brain-regions)--FIX-- and temporal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX--—regions most affected by AD pathology. The mechanisms linking BDNF deficiency to AD include 7(https://www.nature.com/articles/tp2016186) 8(https://link.springer.com/article/10.1186/s40035-022-00279-0):
[amyloid-beta[/entities/[amyloid-beta[/entities/[amyloid-beta[/entities/[amyloid-beta--TEMP--/entities)--FIX-- toxicity: [Aβ[/entities/[amyloid-beta[/entities/[amyloid-beta[/entities/[amyloid-beta--TEMP--/entities)--FIX-- oligomers reduce BDNF expression and disrupt TrkB signaling, creating a feedforward cycle of [synaptic dysfunction[/mechanisms/[synaptic-dysfunction[/mechanisms/[synaptic-dysfunction[/mechanisms/[synaptic-dysfunction--TEMP--/mechanisms)--FIX--
[Tau[/entities/[tau-protein[/entities/[tau-protein[/entities/[tau-protein--TEMP--/entities)--FIX--(/proteins/tau pathology]: BDNF depletion accelerates tau] hyperphosphorylation] through reduced PI3K/Akt signaling and subsequent [GSK-3β[/entities/[gsk3-beta[/entities/[gsk3-beta[/entities/[gsk3-beta--TEMP--/entities)--FIX-- activation
Cholinergic degeneration: BDNF is a key survival factor for [cholinergic] [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- of the [nucleus basalis of Meynert[/brain-regions/[nucleus-basalis-of-meynert[/brain-regions/[nucleus-basalis-of-meynert[/brain-regions/[nucleus-basalis-of-meynert--TEMP--/brain-regions)--FIX--
[neuroinflammation[/mechanisms/[neuroinflammation[/mechanisms/[neuroinflammation[/mechanisms/[neuroinflammation--TEMP--/mechanisms)--FIX--: BDNF deficiency exacerbates microglial/cell-types/[microglia:
Reduced BDNF mRNA and protein levels are found in the substantia nigra of PD patients
Downregulation of TrkB signaling contributes to dopaminergic neuron vulnerability
[alpha-synuclein[/proteins/[alpha-synuclein[/proteins/[alpha-synuclein[/proteins/[alpha-synuclein--TEMP--/proteins)--FIX-- aggregates impair BDNF-TrkB signaling
BDNF supports nigrostriatal dopaminergic neuron survival, and its loss accelerates neurodegeneration
The mutant [huntingtin[/proteins/[huntingtin[/proteins/[huntingtin[/proteins/[huntingtin--TEMP--/proteins)--FIX-- protein] in [Huntington's disease[/mechanisms/[huntington-pathway[/mechanisms/[huntington-pathway[/mechanisms/[huntington-pathway--TEMP--/mechanisms)--FIX-- directly impairs BDNF transcription and axonal transport 1(https://pmc.ncbi.nlm.nih.gov/articles/PMC9138678/):
In [ALS[/diseases/[als[/diseases/[als[/diseases/[als--TEMP--/diseases)--FIX--, BDNF levels are altered in motor [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- and surrounding [glial cells[/entities/[astrocytes[/entities/[astrocytes[/entities/[astrocytes--TEMP--/entities)--FIX--. While BDNF supports motor neuron survival in vitro, [clinical trials[/[clinical-trials[/[clinical-trials[/[clinical-trials[/[clinical-trials[/[clinical-trials[/[clinical-trials[/clinical-trials of BDNF delivery in ALS patients have produced disappointing results, possibly due to difficulties achieving adequate concentrations at motor neuron cell bodies 1(https://pmc.ncbi.nlm.nih.gov/articles/PMC9138678/).
Several approaches to boosting endogenous BDNF production are under investigation 9(https://pmc.ncbi.nlm.nih.gov/articles/PMC12221408/):
Serum and plasma BDNF levels have been investigated as potential [biomarkers] for neurodegenerative diseases. Key findings include 1(https://pmc.ncbi.nlm.nih.gov/articles/PMC9138678/):
The study of Brain Derived Neurotrophic Factor (Bdnf) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying [mechanisms of neurodegeneration[/[mechanisms[/[mechanisms[/[mechanisms[/[mechanisms[/[mechanisms[/[mechanisms[/mechanisms and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.