Neuronal expression of E2F4DN restores adult neurogenesis in homozygous 5xFAD mice via TrkB signaling DOI
Anna Lozano-Ureña,

Aina M. Llabrés-Mas,

Morgan Ramón‐Landreau

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 17, 2024

Abstract The etiology of Alzheimer’s disease (AD) has been associated with impaired neurogenesis in the adult subventricular zone (SVZ), but molecular mechanism leading to this impairment remains poorly understood. Neuronal dysfunction AD-affected brain might lead reduced production neuron-derived paracrine factors acting through receptors necessary for SVZ (ASN). To test hypothesis, we focused on TrkB receptor, which can transduce signals from neurotrophins BDNF and NT4/5, since is known regulate ASN process its function becomes altered AD. Here show that homozygous 5xFAD (h5xFAD) mice. This prevented by administering an AAV.PHP.eB vector expresses neurons transcription factor E2F4 carrying Thr249Ala/Th251Ala mutation (E2F4DN), a gene therapeutic approach previously demonstrated exert multifactorial effects mouse model use culture media conditioned primary cortical expressing E2F4DN was able recover proliferative differentiative capacity neural stem cells (NSCs) isolated h5xFAD effect blocked inhibiting receptor. Accordingly, activation mimicked E2F4DN-conditioned medium NSCs, finding consistent upregulation NT4/5 expression E2F4DN-transduced neurons. We conclude released E2F4DN-expressing phenotype Therefore, includes recovery signaling NSCs.

Language: Английский

A TrkB and TrkC partial agonist restores deficits in synaptic function and promotes activity‐dependent synaptic and microglial transcriptomic changes in a late‐stage Alzheimer's mouse model DOI Creative Commons

Amira Latif‐Hernandez,

Tao Yang, Robert R. Butler

et al.

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(7), P. 4434 - 4460

Published: May 23, 2024

Abstract INTRODUCTION Tropomyosin related kinase B (TrkB) and C (TrkC) receptor signaling promotes synaptic plasticity interacts with pathways affected by amyloid beta (Aβ) toxicity. Upregulating TrkB/C could reduce Alzheimer's disease (AD)‐related degenerative signaling, memory loss, dysfunction. METHODS PTX‐BD10‐2 (BD10‐2), a small molecule partial agonist, was orally administered to aged London/Swedish‐APP mutant mice (APP L/S ) wild‐type controls. Effects on hippocampal long‐term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, RNA sequencing. RESULTS In APP mice, BD10‐2 treatment improved LTP deficits. This accompanied normalized phosphorylation of protein (Akt), calcium‐calmodulin–dependent II (CaMKII), AMPA‐type glutamate receptors containing the subunit GluA1; enhanced activity‐dependent recruitment proteins; increased excitatory synapse number. also had potentially favorable effects LTP‐dependent complement pathway gene transcription. DISCUSSION prevented /Aβ‐associated deficits, reduced abnormalities in synapse‐related transcription genes, bolstered transcriptional changes associated microglial immune response. Highlights Small modulation tropomyosin restores behavior an (AD) model. Modulation TrkB TrkC regulates are candidate targets for translational therapeutics. Electrophysiology combined transcriptomics elucidates restoration. identifies neuron microglia AD‐relevant human‐mouse co‐expression modules.

Language: Английский

Citations

5
From Synaptic Plasticity to Neurodegeneration: BDNF as a Transformative Target in Medicine DOI Open Access
Corneliu Toader,

Matei Serban,

Octavian Munteanu

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(9), P. 4271 - 4271

Published: April 30, 2025

The brain-derived neurotrophic factor (BDNF) has become one of the cornerstones neuropathology, influencing synaptic plasticity, cognitive resilience, and neuronal survival. Apart from its molecular biology, BDNF is a powerful target for transformative benefit in precision medicine, leading to innovative therapeutic approaches neurodegenerative psychiatric diseases like Alzheimer's disease (AD), Parkinson's (PD), major depressive disorder (MDD), post-traumatic stress (PTSD). Nevertheless, clinical applicability obstructed by hurdles delivery, patient-specific diversity, pleiotropic signaling. Here, we summarize findings research, including regulatory pathways diagnostic/prognostic biomarkers integrative approaches. We describe delivery systems, such as lipid nanoparticle-based mRNA therapies CRISPR-dCas9-based epigenetic editing that bypass obstacles BBB (blood-brain barrier) enzymatic degradation. recent implementation multiplex panels combining biodynamic indicators with tau amyloid-β signaling markers showcases novel levels specificity both early detection potential monitoring. Humanized preclinical models iPSC-derived neurons organoids point key role neurodeveloping processes, paralleling advances bridging observation environments. Moreover, tools delivering TrkB activators or AI-based dynamic care platforms enable tailored scalable treatments. This review also aims extend framework used understanding BDNF's relevance traditional situating more work detailing actions ischemic tissues gut-brain axis context systemic health. Finally, outline roadmap incorporation BDNF-centered into worldwide healthcare, highlighting ethical issues, equity, interdisciplinary decomposition. heralds new era neuroscience revolutionizing brain health paving way advancement medicine.

Language: Английский

Citations

0
Positive Allosteric Modulators of Trk Receptors for the Treatment of Alzheimer’s Disease DOI Creative Commons
Pontus Forsell,

Cristina Parrado Fernández,

Boel Nilsson

et al.

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(8), P. 997 - 997

Published: July 28, 2024

Neurotrophins are important regulators of neuronal and non-neuronal functions. As such, the neurotrophins their receptors, tropomyosin receptor kinase (Trk) family tyrosine kinases, has attracted intense research interest role in multiple diseases including Alzheimer’s disease been described. Attempts to administer patients have reported, but clinical trials so far hampered by side effects or a lack clear efficacy. Thus, much focus during recent years on identifying small molecules acting as agonists positive allosteric modulators (PAMs) Trk receptors. Two examples successful discovery development PAMs TrkA-PAM E2511 pan-Trk PAM ACD856. reported disease-modifying preclinical models, whereas ACD856 demonstrates both symptomatic effect models. Both reached stage were be safe well tolerated phase 1 studies, albeit with different pharmacokinetic profiles. These two emerging interesting possible novel treatments that could complement existing anti-amyloid monoclonal antibodies for treatment disease. This review aims present concept receptors future option other neurodegenerative cognitive disorders, current data supporting this new concept. Preclinical indicate dual mechanisms, not only enhancers, also tentative neurorestorative function.

Language: Английский

Citations

3
Modifications in the C-terminal tail of TrkC significantly alter neurotrophin-3-promoted outgrowth of neurite-like processes from PC12 cells DOI Creative Commons
Paweł S. Krawczyk, Dagmara Kłopotowska, Janusz Matuszyk

et al.

Biochemistry and Biophysics Reports, Journal Year: 2024, Volume and Issue: 40, P. 101853 - 101853

Published: Oct. 23, 2024

Language: Английский

Citations

0
Neuronal expression of E2F4DN restores adult neurogenesis in homozygous 5xFAD mice via TrkB signaling DOI
Anna Lozano-Ureña,

Aina M. Llabrés-Mas,

Morgan Ramón‐Landreau

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 17, 2024

Abstract The etiology of Alzheimer’s disease (AD) has been associated with impaired neurogenesis in the adult subventricular zone (SVZ), but molecular mechanism leading to this impairment remains poorly understood. Neuronal dysfunction AD-affected brain might lead reduced production neuron-derived paracrine factors acting through receptors necessary for SVZ (ASN). To test hypothesis, we focused on TrkB receptor, which can transduce signals from neurotrophins BDNF and NT4/5, since is known regulate ASN process its function becomes altered AD. Here show that homozygous 5xFAD (h5xFAD) mice. This prevented by administering an AAV.PHP.eB vector expresses neurons transcription factor E2F4 carrying Thr249Ala/Th251Ala mutation (E2F4DN), a gene therapeutic approach previously demonstrated exert multifactorial effects mouse model use culture media conditioned primary cortical expressing E2F4DN was able recover proliferative differentiative capacity neural stem cells (NSCs) isolated h5xFAD effect blocked inhibiting receptor. Accordingly, activation mimicked E2F4DN-conditioned medium NSCs, finding consistent upregulation NT4/5 expression E2F4DN-transduced neurons. We conclude released E2F4DN-expressing phenotype Therefore, includes recovery signaling NSCs.

Language: Английский

Citations

0