Familial frontotemporal dementia-associated presenilin-1 c.548G>T mutation causes decreased mRNA expression and reduced presenilin function in knock-in mice.

Mutations in the presenilin-1 (PSEN1) gene are associated with familial Alzheimer's disease and frontotemporal dementia (FTD). Interestingly, neuropathological analysis of a Belgian FTD family carrying a PSEN1 c.548G> T mutation confirmed neurodegeneration in the absence of amyloid plaques. To investigate the impact of the c.548G> T mutation on presenilin-1 (PS1) function in vivo, we introduced this mutation into the genomic Psen1 locus. The resulting c.548G> T knock-in (KI) mice are viable but express markedly lower levels of Psen1 mRNA and protein in the brain. This reduction is due to production of aberrantly spliced transcripts lacking either exon 6 or exons 6 and 7 and their subsequent degradation via non-sense-mediated decay (NMD); inhibition of NMD by cycloheximide treatment stabilized these transcripts and restored the level of Psen1 mRNA in KI/KI brains. Interestingly, the reduction of Psen1 mRNA expression and the degradation of aberrant Psen1 splice products occur exclusively in the brain but not in other tissues. Consistent with decreased Psen1 expression, gamma-secretase activity was strongly reduced in the cerebral cortex of KI mice, as measured by de novo gamma-secretase-mediated cleavage of APP and Notch. Moreover, PS1 expressed from Psen1 cDNA carrying the c.548G> T mutation displayed normal gamma-secretase activity in cultured cells, indicating that the corresponding p.183G> V amino acid substitution does not affect gamma-secretase activity. Finally, Psen1 c.548G> T-KI/KI; Psen2(-/-) mice exhibited mild spatial memory deficits in the Morris water maze task. Together, our findings demonstrate that the c.548G> T mutation results in a brain-specific loss of presenilin function due to decreased Psen1 mRNA expression.