Unlocking Alzheimer's Disease: The Role of BDNF Signaling in Neuropathology and Treatment

Abstract

Alzheimer's disease (AD) remains one of the most debilitating neurodegenerative disorders, with its pathological hallmark being progressive cognitive decline and memory loss. Recent research has illuminated the crucial role of the brain-derived neurotrophic factor (BDNF) in the central nervous system (CNS), highlighting its impact on neurogenesis, synaptic plasticity, and neuronal survival. Dysregulation of the BDNF signaling axis, particularly the imbalance between its precursor form and mature BDNF, is strongly implicated in the pathophysiology of AD. This review explores the molecular mechanisms through which BDNF modulates AD neuropathology and presents novel therapeutic strategies to activate BDNF signaling. We focus on the potential of BDNF activators, such as TrkB agonists and mimetic molecules, to restore synaptic function and ameliorate cognitive deficits in AD. Furthermore, we examine the challenges in translating these findings into clinical practice, including issues with blood-brain barrier penetration and the need for precise receptor targeting. The review emphasizes the therapeutic potential of repurposed drugs, including statins and metformin, in enhancing BDNF signaling and offers new insights into the future of AD treatment. Ultimately, this work provides a compelling argument for BDNF-based therapies as a promising avenue for mitigating the cognitive decline associated with Alzheimer's disease, signaling a hopeful direction for future research and clinical trials.

Keywords: Alzheimer’s disease; Brain-derived neurotrophic factor; Cholinergic neurons; Neurodegenerative diseases; Statins.

Fig. 1

proBDNF/BDNF signaling: proBDNF is converted to the BDNF, proBDNF activates p75^NTR with sortilin receptor complex, which causes the expression of c-Jun N-terminal kinase (JNK), Ras homolog family member A (RhoA), and nuclear factor kappa B (NF-κB), leading to neuronal survival, neuronal development, and induction of apoptosis. By activating the TrkB receptor, BDNF stimulates the activation of protein kinase B (Akt), phospholipase C gamma (PLC-γ), mitogen-activated protein kinase (MAPK), phosphoinositol triphosphate kinase (PI3K), and protein kinase B (MAPK). Additionally, BDNF enhances the expression of cAMP-response element-binding protein (CREB), which promotes synaptic plasticity, dendritic growth, and apoptosis inhibition

Fig. 2

Pathophysiology of AD: cholinergic dysfunction, metal ion dyshomeostasis, amyloid beta (Aβ), tau protein hyperphosphorylation, and associated oxidative stress contribute in neuronal loss mainly in temporofrontal cortex. These neuropathological changes contribute in the accumulation of Aβ and hyperphosphorylated tau protein to form amyloid plaques and neurofibrillary tangles (NFTs), and the development of AD

Fig. 3

Impairment of BDNF in AD: increase of soluble Aβ inhibits tissue plasminogen activator (tPA) and activates plasminogen activator inhibitor 1 (PAI-1) leading to the reduction of plasmin synthesis and the formation of BDNF. These alterations result in the reduction the formation of BDNF and increasing of proBDNF brain levels with subsequent synaptic dysfunction and the development of cognitive impairment in AD

Fig. 4

Agents that improve BDNF expression: synthetic drugs and botanical agents as well as epigenetic factors enhance the expression of central BDNF