Cortical neurodegeneration caused by <i>Psen1</i> mutations is independent of Aβ

Mutations in the <i>PSEN</i> genes are the major cause of familial Alzheimer's disease, and presenilin (PS) is the catalytic subunit of γ-secretase, which cleaves type I transmembrane proteins, including the amyloid precursor protein (APP) to release Aβ peptides. While PS plays an essential role in the protection of neuronal survival, <i>PSEN</i> mutations also increase the ratio of Aβ42/Aβ40. Thus, it remains unresolved whether <i>PSEN</i> mutations cause AD via a loss of its essential function or increases of Aβ42/Aβ40. Here, we test whether the knockin (KI) allele of <i>Psen1</i> L435F, the most severe FAD mutation located closest to the active site of γ-secretase, causes age-dependent cortical neurodegeneration independent of Aβ by crossing various <i>Psen</i> mutant mice to the <i>App</i>-null background. We report that removing Aβ completely through APP deficiency has no impact on the age-dependent neurodegeneration in <i>Psen</i> mutant mice, as shown by the absence of effects on the reduced cortical volume and decreases of cortical neurons at the ages of 12 and 18 mo. The L435F KI allele increases Aβ42/Aβ40 in the cerebral cortex while decreasing de novo production and steady-state levels of Aβ42 and Aβ40 in the presence of APP. Furthermore, APP deficiency does not alleviate elevated apoptotic cell death in the cerebral cortex of <i>Psen</i> mutant mice at the ages of 2, 12, and 18 mo, nor does it affect the progressive microgliosis in these mice. Our findings demonstrate that <i>Psen1</i> mutations cause age-dependent neurodegeneration independent of Aβ, providing further support for a loss-of-function pathogenic mechanism underlying <i>PSEN</i> mutations.