Integrative hdWGCNA and multi-model validation identify BAIAP2 as a shared neuronal hub for cognitive impairment acrossAlzheimer's disease, diabetic encephalopathy and brain aging
Year: 2026
Type: preprint
Abstract: Alzheimer’s disease (AD), diabetic encephalopathy (DE), and brain aging converge on cognitive decline with overlapping synaptic damage, impaired neuronal plasticity, and hippocampal circuit dysfunction. However, whether these pathological states share a unified neuronal transcriptional architecture remains largely unexplored at single-cell resolution. Integrating single-cell transcriptomic datasets related to AD, DE, and brain aging from the GEO database with high-dimensional weighted gene co-expression network analysis, we identified a conserved neuronal module and hub genes shared across the pathological conditions, pinpointing BAIAP2/IRSp53 as the sole shared neuronal core gene. In vivo , mouse models of all three cognitive disorders exhibited significant spatial memory deficits and consistent downregulation of hippocampal BAIAP2 at both the mRNA and protein levels; immunofluorescence further confirmed a widespread reduction of BAIAP2 in the hippocampal CA1, CA3, and dentate gyrus regions. In vitro , amyloid-β, metabolic stress, and senescence-inducing stimuli each recapitulated BAIAP2 suppression in SH-SY5Y neurons. Collectively, we establish BAIAP2 as a critical synaptic scaffolding hub whose disruption represents a unified neuronal substrate linking neurodegeneration, metabolic brain injury, and brain aging. These findings identify BAIAP2 as a potential target for AD-spectrum therapeutic strategies against cognitive decline.
Source: Research Square
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7225167343