Neurotrophin Crosstalk in the Etiology and Treatment of Neuropsychiatric and Neurodegenerative Disease

Abstract

This article reviews the current progress in our understanding of the mechanisms by which growth factors, including brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and select neurotrophin-regulated gene products, such as VGF (non-acronymic) and VGF-derived neuropeptides, function in the central nervous system (CNS) to modulate neuropsychiatric and neurodegenerative disorders, with a discussion of the possible therapeutic applications of these growth factors to major depressive disorder (MDD) and Alzheimer's disease (AD). BDNF and VEGF levels are generally decreased regionally in the brains of MDD subjects and in preclinical animal models of depression, changes that are associated with neuronal atrophy and reduced neurogenesis, and are reversed by conventional monoaminergic and novel ketamine-like antidepressants. Downstream of neurotrophins and their receptors, VGF was identified as a nerve growth factor (NGF)- and BDNF-inducible secreted protein and neuropeptide precursor that is produced and trafficked throughout the CNS, where its expression is greatly influenced by neuronal activity and exercise, and where several VGF-derived peptides modulate neuronal activity, function, proliferation, differentiation, and survival. Moreover, levels of VGF are reduced in the CSF of AD subjects, where it has been repetitively identified as a disease biomarker, and in the hippocampi of subjects with MDD, suggesting possible shared mechanisms by which reduced levels of VGF and other proteins that are similarly regulated by neurotrophin signaling pathways contribute to and potentially drive the pathogenesis and progression of co-morbid neuropsychiatric and neurodegenerative disorders, particularly MDD and AD, opening possible therapeutic windows.

Keywords: ADNP (activity dependent neuroprotective protein); Alzheimer’s disease; BDNF (brain derived neurotrophic factor); MDD (major depressive disorder); TLQP-62; TrkB; VEGF – vascular endothelial growth factor; VGF.

FIGURE 1

Antidepressant efficacy of therapeutics, delivered to CNS via intracortical, intrahippocampal, intracerebroventricular, and intranasal routes, that target neurotrophin signaling pathways. Panels (A,B) depict intracerebroventricular (icv), intracortical, or intrahippocampal infusions of neuropeptide TLQP-62 or AAV-VGF into rodent brain, while panel (C) depicts intranasal administration of small molecule agonists, including the TrkB agonist LM22A-4, and neuropeptides, such as TLQP-62, for delivery of pharmacotherapeutics to the CNS. Proposed diffusion pathways of agents delivered intranasally, bypassing the blood-brain-barrier (BBB), for distal delivery via the CSF and the perivascular spaces around cranial nerves, to the various brain regions shown in panel (D). In panel (E), the antidepressant-like actions of TLQP-62 are shown to be mediated through an unknown receptor (in gray), leading to activation of known glutamatergic signaling pathways, including NMDAR and mGluR5 (Thakker-Varia et al., 2014), the BDNF/TrkB signaling cascade (Jiang et al., 2019a), and calcium channels which activate GluR1 (Jiang et al., 2019a). Other BDNF mimetic/agonists, including LM22A-4 (Fletcher et al., 2021) and 7,8-DHF (Wurzelmann et al., 2017), have shown antidepressant efficacy via TrkB activation. Additionally, vascular endothelial growth factor (VEGF) is shown to induce antidepressant effects via PI3K/PKB/mTORC1 pathways that activate CREB. Activated CREB increases BDNF and VGF transcription, leading to increased BDNF and VGF translation and secretion, and stimulation of BDNF/TrkB signaling – an autoregulatory loop.

FIGURE 2

Schematic of the Comorbidity of Major Depressive Disorder (MDD) and Alzheimer’s disease (AD), disorders that share pathophysiology, disease mechanisms, and potentially treatments. MDD and AD are often comorbid, in many cases sharing a number of pathophysiological features that are summarized in this figure. Cognitive disorders are a core feature of both MDD and AD, often referred to in MDD as pseudodementia or dementia of depression. Cognitive symptoms (particularly memory) in MDD can be reversible with treatment, or more commonly can persist following improvement or remission of depressive symptoms, progressing to overt dementia and AD (Rodrigues et al., 2014; Perini et al., 2019). Immune and glucocorticoid dysfunction are common to AD and MDD, leading to neuronal atrophy, as depicted. Expression of neurotrophic growth factors, including BDNF, VEGF, and VGF, and neuropeptides, such as TLQP-62, is also reduced in both AD and MDD. Treatment with antidepressants and increased exercise increase the levels of neurotrophins in MDD, helping to rescue neuronal function. In AD, exercise and future novel therapeutics may be similarly utilized to increase levels of these neurotrophins and select downstream gene products (VGF), halting the progression of neurodegenerative disease.