The observation that PS-1 and PS-2 are highly expressed in neurons, localized to the endoplasmic reticulum, suggests that the presenilins could regulate neuronal K+ channel expression; mutations in PS-1/PS-2 would then be expected to result in profound changes in neuronal excitability and contribute to the cognitive decline commonly associated with Alzheimer's Disease.
Although hyperactivity and hypersynchronicity were respectively detected in mice expressing the PS2-N141I or the APP Swedish mutant alone, the increase in cross-frequency coupling specifically characterized the 6-month-old PS2APP mice, just before the surge of the cognitive decline.
In addition, a 58-year-old female with a 2 year course of cognitive decline and no family history of dementia has abnormal fludeoxyglucose-positron emission tomography imaging and a novel 2 base pair deletion in presenilin 2 at nucleotide 342/343, predicted to produce a frame-shift and premature termination.