Abstract
Alzheimer’s disease (AD; Tuapaemahara) is the most common form of dementia (mate wareware), affecting millions of people worldwide and presents a major public health challenge due to the lack of effective disease-modifying treatments. Synaptic dysfunction is an early hallmark of AD pathogenesis, preceding the widespread neuron loss and cognitive decline characteristic of the disease. This dysfunction is driven by the accumulation of amyloid-β and tau pathologies, which disrupt synaptic plasticity by interfering with glutamate receptor function. This early synaptic vulnerability suggests that enhancing synaptic efficacy may be a promising target in the development of effective therapeutics for AD.
Secreted amyloid precursor protein alpha (sAPPα), an endogenous neuromodulator derived from the amyloid precursor protein (APP), exhibits neuroprotective, neurotrophic and memory-enhancing properties and has been demonstrated to rescue synaptic plasticity deficits in rodent models of AD. These beneficial properties position sAPPα as an exciting emerging therapeutic avenue for developing a disease-modifying therapy for AD. Furthermore, CTα16 and AβCore, bioactive sAPPα-derived peptides, have recently been shown to recapitulate aspects of sAPPα’s plasticity-enhancing effects and may represent a more viable therapeutic avenue due to their small size. However, the precise molecular mechanisms harnessed by sAPPα and sAPPα-derived peptides or their efficacy in human neurons are not yet fully elucidated.
To further our understanding of sAPPα and sAPPα-derived peptides plasticity-promoting effects, we examined the transcription, translation and surface expression of key plasticity-related N-methyl-D-aspartate receptor (NMDAR) subunits in cultured rodent hippocampal neurons over time, examining its early and enduring effects. To further investigate sAPPα as a novel therapeutic agent for AD, we examined the ability of sAPPα and the sAPPα-derived peptide, CTα16, to alter global protein synthesis and NMDAR surface expression in excitatory and inhibitory iPSC-derived human neurons.
Using a combination of immunocytochemistry, Fluorescent Non-Canonical Amino Acid Tagging with Proximity Ligase Assay (FUNCAT-PLA), and Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) techniques, we have shown that sAPPα induces the biphasic enhancement of surface de novo GluN2B-containing NMDARs in the neuronal dendrites. Furthermore, we found that sAPPα and CTα16 exhibit distinct yet overlapping patterns of NMDAR subunit gene regulation in rodent neurons and enhance both protein synthesis and surface expression of GluN2B in a time- and cell-type-specific manner in human iPSC-derived neurons.
These findings complement established understanding that sAPPα rapidly traffics AMPARs, priming the synapse for activity, suggesting NMDARs may contribute to this priming action and support sustained synaptic changes. Differential responses in excitatory versus inhibitory iPSC-derived human neurons suggest sAPPα may target the excitatory-inhibitory imbalance implicated in early-AD. Demonstrating efficacy in human neuronal models represents a critical step toward translating sAPPα-based therapies for AD.