NPTX2 is a synaptic immediate early gene essential for long-term synaptic plasticity and excitatory-inhibitory balance 1. NPTX2 regulates AMPA receptor subunit GluA4 expression on parvalbumin interneurons, critical for controlling network excitability and rhythmicity 1. The protein also functions as a secreted neuronal pentraxin that binds complement C1q, restraining microglial-mediated synapse loss 2. NPTX2 is part of an activity-regulated plasticity cluster coordinating synaptic function and mitochondrial integrity 3. In disease, NPTX2 misregulation is central to TDP-43 proteinopathies in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, where TDP-43 normally regulates NPTX2 via its 3' UTR 4. NPTX2 accumulation from TDP-43 loss of function drives neurodegeneration, while NPTX2 reduction worsens complement-mediated pathology 2. Cerebrospinal fluid NPTX2 levels are robust biomarkers predicting cognitive decline in Alzheimer's disease, with SNAP-25/NPTX2 and 14-3-3ζ/δ/NPTX2 ratios predicting progression better than either protein alone 56. NPTX2 loss of function also disrupts sleep-wake regulation and circadian rhythmicity 7. These findings position NPTX2 as a hub linking synaptic dysfunction to cognitive decline across multiple neurodegenerative diseases.