Impaired cholinergic function and an enhanced glymphatic component in the nucleus basalis of Meynert in individuals with Prader-Willi syndrome

The nucleus basalis of Meynert (NBM) is a major cholinergic hub essential for cognitive and behavioral functioning. Degeneration of acetylcholine‑producing neurons in the NBM is a hallmark of several neurological disorders. Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder caused by loss of expression of paternally expressed imprinted genes on chromosome 15q11-q13. Individuals with PWS exhibit intellectual disability, social and emotional dysfunction, muscular hypotonia, hyperphagia, and obesity. To investigate whether the NBM is affected in PWS, we analyzed postmortem NBM tissue from 8 individuals with PWS (paternal deletions) and 16 well‑matched controls. The NBM cholinergic system was analysed using choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), and neuronal integrity and activity were assessed using Golgi membrane protein 130 (GM130) and brain-derived neurotrophic factor (BDNF). Markers of potential neurodegeneration (AT8 and amyloid‑β) were evaluated, alongside glial alterations including microglia (Iba1), astrocytes (GFAP), and the glymphatic component aquaporin‑4 (AQP4). PWS cases showed a marked, statistically significant, reduction in ChAT‑positive neurons in the NBM, accompanied by increased AQP4 immunoreactivity, indicating a possible acetylcholine deficit and glymphatic alteration in the forebrain. These findings identify a cholinergic vulnerability in PWS and suggest that impaired cholinergic signaling may contribute to the cognitive and behavioral phenotype. Improving cholinergic tone may represent a potential therapeutic strategy to improve quality of life in individuals with PWS.