A Closed-Loop System for Real-Time Seamless Replacement of Apoptotic Neurons: A Scientific Hypothesis for Reversing Irreversible Adult Neuronal Loss and Cognitive Aging

Irreversible loss of neurons in the adult mammalian central nervous system is a core driver of cognitive decline, yet existing "repair after damage" strategies cannot reverse established injury. Here, we propose a disruptive hypothesis: utilizing mitochondrial outer membrane permeabilization (MOMP) as the molecular switch for "irreversible" apoptosis, we construct a closed-loop system for real-time seamless replacement of apoptotic neurons. The system comprises two core modules: a labeling module that performs specific membrane modification (PS acetylation) on neurons at the earliest stage of irreversible apoptosis, and a replacement module (engineered autologous neural progenitor cells) that precisely targets apoptotic sites via dual-signal recognition (modified PS + chemokine CX3CL1), accomplishing timed clearance of apoptotic debris and in situ neuronal differentiation before cellular disintegration, achieving "zero-latency replacement." The core innovation of this hypothesis lies in not pursuing "pixel-level replication" of the apoptotic neuron's connections. Instead, it relies on the nervous system's inherent plasticity: after precise delivery of newborn neurons to the apoptotic site, subsequent synapse outgrowth, competition, and stabilization are accomplished by the neuron's intrinsic growth programs and local network activity-dependent plasticity. The human nervous system is inherently in a state of continuous synaptic turnover and remodeling; newborn neurons, as participants in this dynamic process, will manifest their functional contributions over time. Therefore, even partial synaptic functional replacement is sufficient to make a substantial contribution to neural network homeostasis—this itself represents a paradigm shift from 0 to 1. All core designs of this hypothesis are grounded in established consensus findings, with clear stepwise validation pathways and strict falsifiability, providing a novel theoretical framework for neural repair and intervention in cognitive aging.