Presenilin 1 hemizygosity has no overt deleterious phenotypic outcomes in sheep: Potential implications for therapeutic targets in Alzheimer’s disease

Neurobiol Aging. 2025 Apr 25;152:25-33. doi: 10.1016/j.neurobiolaging.2025.04.006. Online ahead of print.

ABSTRACT

Alzheimer’s disease (AD) is a neurodegenerative condition and one of the most significant medical challenges today. Dominant mutations causing early-onset AD have been identified in the presenilin 1 and 2 (PSEN1 and PSEN2), and the amyloid precursor protein (APP) genes. Either PSEN1 or PSEN2 is required by γ-secretase, a functional complex that cleaves APP to produce amyloid-beta (Aβ) peptides of varying lengths. These mutations result in relative or absolute increases in the longer Aβ peptides (Aβ_1-40, Aβ _1-42), which accumulate as plaques, characteristic of both early and late-onset AD. To investigate the effects of modulating PSEN1 expression, we have produced PSEN1 hemizygous sheep. Sheep PSEN and APP genes are highly conserved relative to humans, including the APP proteolytic cleavage sites, and like humans, sheep naturally develop plaques and TAU tangles with age. At five years of age, the PSEN1 hemizygous animals are phenotypically and biochemically normal. Interestingly, the characteristic Aβ peptide levels in their cerebrospinal fluid and plasma remain at wildtype levels, indicating that a 50 % reduction in PSEN1 abundance does not materially affect γ-secretase’s APP cleavage activity. These results suggest that generalized regulation of PSEN1 expression is unlikely to be an effective therapeutic approach for AD on its own. However, it does suggest that loss of one PSEN1 allele may be tolerated in higher organisms, with no deleterious side-effects. It is therefore possible that knocking-out or knocking-down one copy of PSEN1 via genetic modification will be tolerated in humans, especially as functional hemizygous humans are present in the population (gnomad). These kinds of therapies could potentially prevent AD caused by dominant gain-of-function mutations in PSEN1.

PMID:40315540 | DOI:10.1016/j.neurobiolaging.2025.04.006