Brain delivery of a neurotrophic peptide derived from secreted amyloid precursor protein APPsα as a therapeutic strategy for Alzheimer's disease
Alzheimer's disease (AD) is characterized by extracellular Amyloid β (Aβ) plaque deposition and the accumulation of hyperphosphorylated Tau species. Whereas neurotoxic Aβ is derived from amyloid precursor protein (APP) by β- and γ-secretase cleavage, APP processing along the non-amyloidogenic p...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
2026
|
| In: |
Journal of controlled release
Year: 2026, Volume: 389, Pages: 1-23 |
| ISSN: | 1873-4995 |
| DOI: | 10.1016/j.jconrel.2025.114374 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.jconrel.2025.114374 Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S0168365925009885 
|
| Author Notes: | Lena Rehra, Susanne Erdinger, Lelia Wagner, Danny Baltissen, Jennifer Just, Leo König, Eric Mühlberg, Tom Eisenzapf, Lara Kilian, Marija Banicevic, Verena Bengelsdorff, Christian J. Buchholz, Walter Mier, Philipp Uhl, Martin Korte, Gert Fricker, Ulrike C. Müller |
| Summary: | Alzheimer's disease (AD) is characterized by extracellular Amyloid β (Aβ) plaque deposition and the accumulation of hyperphosphorylated Tau species. Whereas neurotoxic Aβ is derived from amyloid precursor protein (APP) by β- and γ-secretase cleavage, APP processing along the non-amyloidogenic pathway results in the secretion of the large neurotrophic ectodomain APPsα. In AD, synapse dysfunction and loss are highly correlated with cognitive decline. However, therapeutic strategies to prevent or reverse synaptic loss remain elusive. Here, we examined the potential of a short C-terminal peptide (CTα16) derived from APPsα to mitigate synaptic deficits in AD model and knockout mice. We tested two different delivery systems and routes of administration: local delivery on the genetic level with AAV9 vectors and nanocarrier-mediated systemic delivery of the peptide. For genetic delivery (AAV-iCTα16), the CTα16 peptide was fused to the pre-pro-domain of thyrotropin-releasing hormone (TRH) leading to processing within the secretory pathway, enabling efficient peptide expression and secretion in vitro and in vivo. When injected into the hippocampus of APP/APLP2-deficient NexCre cDKO mice AAV-iCTα16 fully rescued spine density and synaptic plasticity (LTP), which identifies the CTα16 peptide as a major functional domain of neurotrophic APPsα in vivo. Further, we show that AAV-iCTα16 reverses synaptic impairments of aged THY-Tau22 model mice in the presence of pre-established Tau pathology. For peptide delivery to the brain, we developed CTα16 encapsulating liposomes decorated with either the cell-penetrating peptide CycR9 or an α-Transferrin receptor (TfR) antibody for blood-brain barrier (BBB) crossing. Strikingly, intravenous injection of CTα16-liposomes again efficiently restored spine density in aged THY-Tau22 mice to a similar level as AAV-iCTα16. Together, these data suggest that brain delivery of CTα16 can reverse synaptic damage and enhance functional plasticity of the neuronal network and thus holds therapeutic potential for tauopathies in general and AD in particular. |
|---|---|
| Item Description: | Online veröffentlicht: 2 November 2025 Gesehen am 20.05.2026 |
| Physical Description: | Online Resource |
| ISSN: | 1873-4995 |
| DOI: | 10.1016/j.jconrel.2025.114374 |