{"entity":{"id":"dlg4-psd95","kind":"target","name":"DLG4 (PSD-95)","aka":["PSD-95","PSD95","SAP90","postsynaptic density protein 95","DLG4"],"tldr":"The main scaffold protein on the receiving side of brain synapses. Losing synapses tracks memory decline in Alzheimer's disease, but today's synapse PET scans only see the sending side (SV2A). No tracer for PSD-95 has been published, so the receiving side cannot yet be imaged.","summary":"DLG4 (HGNC:2903) encodes postsynaptic density protein 95, the scaffold that anchors glutamate receptors in the postsynaptic density of excitatory synapses. Synapse loss is an early event in Alzheimer's disease and is closely linked to cognitive decline, and PSD-95 is one of the proteins that falls. In post-mortem brain from the Banner Sun Health Research Institute, PSD-95 was lower in every region studied in Alzheimer's dementia than in controls without dementia (not significant in the hippocampus), and PSD-95 levels correlated with tangle and plaque density and with Mini Mental State Examination scores. In cerebrospinal fluid, a Massachusetts General Hospital study of two cohorts (178 and 156 people) found PSD-95 raised in Alzheimer's disease but not specific to it.\n\nSynaptic density PET today images the presynaptic vesicle protein SV2A with tracers such as 11C-UCB-J, used for example to follow synapse loss in animal models. A PubMed search on 24 September 2026 for PSD-95 or DLG4 together with PET, SPECT, radioligand or radiotracer returned 17 records, and none described a radioligand that binds PSD-95 itself.\n\nThat absence is the point of this record. PSD-95 is an intracellular scaffold rather than a receptor, so a tracer would need to cross the blood-brain barrier and the cell membrane and bind a protein-protein interaction domain, which is harder than binding a vesicle protein. The unmet need is a postsynaptic counterpart to SV2A PET that could separate loss of receiving sites from loss of transmitting sites.","asOf":"2026-09-24","links":[{"label":"HGNC: DLG4 gene record (HGNC:2903)","url":"https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:2903"},{"label":"Serrano et al., Int J Mol Sci 2024: presynaptic and postsynaptic proteins against pathology in Alzheimer's disease (PMID 38542104)","url":"https://pubmed.ncbi.nlm.nih.gov/38542104/"},{"label":"Kivisäkk et al., Alzheimers Res Ther 2022: PSD-95, SNAP-25 and neurogranin in CSF (PMID 35461266)","url":"https://pubmed.ncbi.nlm.nih.gov/35461266/"},{"label":"PubMed search used for the absence statement: PSD-95/DLG4 with PET, SPECT, radioligand or radiotracer","url":"https://pubmed.ncbi.nlm.nih.gov/?term=%28%22PSD-95%22%5Btiab%5D+OR+PSD95%5Btiab%5D+OR+DLG4%5Btiab%5D%29+AND+%28PET%5Btiab%5D+OR+radioligand%5Btiab%5D+OR+radiotracer%5Btiab%5D+OR+radiolabeled%5Btiab%5D+OR+radiolabelled%5Btiab%5D+OR+SPECT%5Btiab%5D%29"}],"tags":["neurology","synaptic density","no tracer yet","unmet need"],"related":["alzheimers-disease","amyloid-beta","tau-protein","pet","c-11"],"indications":["alzheimers-disease"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"symbol":"DLG4","biology":"A membrane-associated guanylate kinase scaffold in the postsynaptic density of excitatory synapses. Its PDZ domains bind NMDA-receptor subunits and other partners, so its level is a proxy for the number of postsynaptic sites.","whereFound":["Excitatory synapses throughout the brain, concentrated in the postsynaptic density","Reduced across cortical regions in Alzheimer's dementia in post-mortem brain","Detectable in cerebrospinal fluid, raised in Alzheimer's disease and in some inflammatory, vascular and other neurodegenerative conditions"],"targetClass":"other","prevalence":[]},"route":"/targets/dlg4-psd95/","neighbours":{"indication":[{"id":"alzheimers-disease","kind":"indication","name":"Alzheimer's disease","route":"/indications/alzheimers-disease/"}],"target":[{"id":"amyloid-beta","kind":"target","name":"Amyloid beta plaques","route":"/targets/amyloid-beta/"},{"id":"tau-protein","kind":"target","name":"Tau protein (neurofibrillary tangles)","route":"/targets/tau-protein/"}],"technology":[{"id":"pet","kind":"technology","name":"PET (positron emission tomography)","route":"/technologies/pet/"}],"isotope":[{"id":"c-11","kind":"isotope","name":"Carbon-11","route":"/isotopes/c-11/"}]}}