Patent ID: 7271313

Claim:
A presenilin-deficient mouse made by a method comprising: (a) making a first recombinantly engineered mouse whose genomic DNA comprises: (i) homozygous modified endogenous presenilin-1 alleles in which one or more exons of each presenilin-1 allele are flanked by lox P elements in such a manner that, upon exposure to Cre recombinase, said one or more exons are excised from said genomic DNA; (ii) a DNA sequence element coding for Cre recombinase under the control of a CaM kinase II promoter; (b) producing or obtaining a second recombinantly engineered mouse, whose genomic DNA comprises homozygous modified endogenous presenilin-2 alleles in which one or more exons have been interrupted by the introduction of an exogenous sequence that prevents each presenilin-2 allele from expressing a functional protein; (c) crossbreeding said first recombinantly engineered mouse with said second recombinantly engineered mouse to produce a progeny mouse whose genomic DNA comprises a presenilin-1 allele with exons flanked by loxP elements as described above in paragraph (a)(i); a DNA sequence element coding for Cre recombinase as described in paragraph (a)(ii); and a presenilin-2 allele in which one or more exons have been interrupted as described in paragraph (b); (d) further breeding said progeny mouse to produce a presenilin-deficient mouse whose genomic DNA comprises homozygous presenilin-1 alleles with exons flanked by loxP elements as described in paragraph (a)(i); a DNA sequence element coding for Cre recombinase as described in paragraph (a)(ii); and homozygous presenilin-2 alleles in which one or more exons have been interrupted as described in paragraph (b); and wherein, at some time after birth and prior to death, said presenilin-deficient mouse comprises within the genome of cells having CaM kinase II promoter activity a homozygous deletion within its presenilin-1 alleles such that, compared to a wild type mouse, said presenilin-deficient mouse is: (i) deficient in presenilin-1 in those cells where the CaM kinase II promoter is active; (ii) does not express presenilin-2; and (iii) exhibits age-dependent synaptic and neuronal degeneration and age-related memory impairment.