Abstract: Alzheimer’s disease is characterized by hippocampal neuronal apoptosis, which leads to cognitive decline. The pathophysiology of Alzheimer’s disease is largely driven by disrupted cellular metabolism and insufficient neuronal energy supply. However, current treatments for Alzheimer’s disease remain limited because of side effects and disease complexity. Increasing evidence suggests that amyloid-β oligomer-induced neuronal insulin resistance and metabolic dysfunction play key roles in Alzheimer’s disease progression, yet their underlying mechanisms and therapeutic strategies remain unclear. In this translational preclinical study, we combined a case-control analysis, in vitro cell assays, and in vivo experiments using amyloid precursor protein/presenilin 1 transgenic mice to investigate whether transcriptional regulation of key regulatory factors restores neuronal energy supply and improves Alzheimer’s disease-induced pathology. The case-control analysis identified pre-B-cell leukemia transcription factor 1 as a crucial regulator of brain metabolic homeostasis in Alzheimer’s disease. We developed a blood–brain barrier-permeable trans-activator of transcription-pre-B-cell leukemia transcription factor 1 fusion protein to enhance pre-B-cell leukemia transcription factor 1 expression, with the aim of restoring neuronal energy supply and reducing apoptosis. Mechanistic investigations using Alzheimer’s disease models revealed that pre-B-cell leukemia transcription factor 1 transcriptionally upregulates insulin receptor substrate 1 by interacting with its promoter, which resulted in augmented insulin signaling. Trans-activator of transcription-pre-B-cell leukemia transcription factor 1 downregulated PDK4, significantly upregulated the expression of pyruvate dehydrogenase, and promoted mitochondrial oxidative phosphorylation activity, which inhibited the abnormally enhanced glycolytic flux, increased adenosine triphosphate production, and ultimately helped restore neuronal energy homeostasis. Therapeutic administration of trans-activator of transcription-pre-B-cell leukemia transcription factor 1 in amyloid precursor protein/presenilin 1 transgenic mice significantly enhanced cognitive performance, diminished hippocampal neuronal apoptosis, and mitigated amyloid-β deposition. No significant hepatotoxicity, nephrotoxicity, or other detectable adverse effects were observed within the dose ranges and time windows of administration. Taken together, we identified pre-B-cell leukemia transcription factor 1 as a crucial transcriptional regulator of neuronal energy metabolism in Alzheimer’s disease. Moreover, we elucidated the molecular mechanism through which the pre-B-cell leukemia transcription factor 1–insulin receptor substrate 1 signaling axis sustains metabolic homeostasis. Furthermore, we demonstrated that the blood–brain barrier-permeable trans-activator of transcription-pre-B-cell leukemia transcription factor 1 fusion protein constitutes a mechanistically innovative and highly translatable therapeutic strategy for Alzheimer’s disease. 

Key words: Alzheimer’s diseasel amyloid-beta oligomersl amyloid precursor protein/presenilin 1l insulin receptor substrate 1l insulin resistancel metabolic reprogrammingl molecular medicinel neuronl oxidative phosphorylationl pre-B-cell leukemia transcription factor 1