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Defining the molecular changes that underlie Alzheimer’s disease (AD) is an important question in neuroscience. Here, we examined changes in protein SUMOylation, and proteins involved in mitochondrial dynamics, in an in vitro model of AD induced by application of amyloid-β 1–42 (Aβ1–42) to cultured neurons. We observed Aβ1–42-induced decreases in global SUMOylation and in levels of the SUMO pathway enzymes SENP3, PIAS1/2, and SAE2. Aβ exposure also decreased levels of the mitochondrial fission proteins Drp1 and Mff and increased activation of caspase-3. To examine whether loss of SENP3 is cytoprotective we knocked down SENP3, which partially prevented the Aβ1–42-induced increase in caspase-3 activation. Together, these data support the hypothesis that altered SUMOylation may play a role in the mechanisms underlying AD.