Progress toward valid transgenic mouse models for Alzheimer’s disease

Abstract

A transgenic mouse model for Alzheimer’s disease (AD) should mimic the age-dependent accumulation of β-amyloid plaques, neurofibrillary tangles, neuronal cell death as well as display memory loss and behavioral deficits. Age-dependent accumulation of Aβ deposits in mouse brain has been achieved in mice overexpressing mutant alleles of the amyloid precursor protein (APP). In contrast, mice bearing mutant alleles of the presenilin genes show increased production of the Aβ42 peptide, but do not form amyloid deposits unless mutant alleles of APP are also overproduced. Furthermore, the onset of Aβ deposition is greatly accelerated, paralleling the involvement of presenilins in early onset AD. Studies of APP and presenilin transgenic mice have shown 1) the absence of a requirement for a maturation step in dense core plaque formation, 2) evidence that β-amyloid deposition is directed by regional factors, and 3) behavioral deficits are observed before Aβ deposition. Crosses of APP transgenic mice with mice modified for known AD risk factors and “humanizing” the mouse may be necessary for complete replication of AD.