Molecular cloning, expression, and regulation of hippocampal amyloid precursor protein of senescence accelerated mouse (SAMP8)

Alzheimer's disease (AD) is associated with increased expression of amyloid precursor protein (APP) with a consequent deposition of amyloid beta pepti de (A beta) which forms characteristic senile plaques. We have noticed that the senescence accelerated mouse (SAMP8), a strain of mouse that exhibits age-dependent defects such as loss of memory and retention at an early age of 8-12 months, also produces increased amounts of APP and A beta similar t o those observed in Alzheimer's disease (AD). In order to investigate if th is is due to mutations in APP similar to those observed in AD, and to devel op molecular probes that regulate its expression, APP cDNA was cloned from the hippocampus of 8-month-old SAMP8 mouse. The nucleotide sequence is 99.7 % homologous with that of mouse and rat, 88.7% with monkey, and 89.2% with human homologues. At the amino acid level, the homology was 99.2% and 97.6% with rodent and primate sequences, respectively. A single amino acid subst itution of Alanine instead of Valine at position 300 was unique to SAMP8 mo use APP. However, no mutations similar to those reported in human familial AD were observed. When the cDNA was expressed in HeLa cells, glycosylated m ature APP could be detected by immunoblotting technique. The expression cou ld be regulated in a time- and concentration-dependent manner by using an a ntisense oligonucleotide specific to APP mRNA. Such regulation of APP expre ssion may have a therapeutic application in vivo.