FAD mutant PS-1 gene-targeted mice: increased Aβ42 and Aβ deposition without APP overproduction

Abstract To investigate the consequences of mutant presenilin-1 (PS-1) expression under the control of the normal PS-1 gene, a gene-targeted mouse bearing the FAD mutation P264L was made. Gene-targeted models are distinct from transgenic models because the mutant gene is expressed at normal levels, in the absence of the wild-type protein. PS-1 P264L/P264L mice had normal expression of PS-1 mRNA, but levels of the N- and C-terminal protein fragments of PS-1 were reduced while levels of the holoprotein were increased. When crossed into Tg(HuAPP695.K670N/M671L)2576 mice, the PS-1 P264L mutation accelerated the onset of amyloid (Aβ) deposition in a gene-dosage dependent manner. Tg2576/PS-1 P264L/P264L mice also had Aβ deposition that was widely distributed throughout the brain and spinal cord. APP NLh/NLh /PS-1 P264L/P264L double gene-targeted mice had elevated levels of Aβ42, sufficient to cause Aβ deposition beginning at 6 months of age. Aβ deposition increased linearly over time in APP NLh/NLh /PS-1 P264L/P264L mice, whereas the increase in Tg2576 mice was exponential. The APP NLh/NLh /PS-1 P264L/P264L double gene-targeted mouse represents an animal model that exhibits Aβ deposition without overexpression of APP.