SAMP10 mouse is a model of brain aging in which senescence is characterized by cerebral atrophy most prominent in the frontal cortex, deterioration in performance of learning and memory tasks, and alterations of the central dopaminergic system. The present study investigates age-related changes in the expression of synapse-related proteins to determine whether the number of synapses is decreased in SAMP10 mice. We quantified expression levels of synaptophysin, a presynaptic protein, and of PSD-95, a postsynaptic protein in various brain regions by immunoblotting. Both synapse-related proteins (52% of synaptophysin and 55% of PSD-95) were lost from the anterior cerebral cortex in SAMP10 mice at age 10–12 months compared with those in mice at age 3 months. Synaptophysin was lost by 30% from the posterior cerebral cortex of SAMP10 mice at age 15–16 months. The level of synaptophysin, but not of PSD-95 decreased by about 25% in the brain stem of SAMP10 mice aged 7 and 10–12 months. A loss of synapse-related proteins was not significant in other brain regions. Age-related loss of synaptophysin or PSD-95 was not evident in normal aging control SAMR1 mice that do not develop brain atrophy. In summary, synapses were lost with aging in SAMP10 mice and the synaptic loss was most prominent in the anterior cerebral neocortex. Since a loss of neocortical synapses is the primary correlate with the intellectual decline in human neurodegenerative diseases, SAMP10 mouse is a useful model with which to study the mechanisms underlying synaptic loss in human neurodegenerative dementias. Synapse 48:198–204, 2003. © 2003 Wiley-Liss, Inc.