DBA/2J genetic background exacerbates spontaneous lethal seizures but lessens amyloid deposition in a mouse model of Alzheimer's disease.
Alzheimer's disease (AD) is a leading cause of dementia in the elderly and is characterized by amyloid plaques, neurofibrillary tangles (NFTs) and neuronal dysfunction. Early onset AD (EOAD) is commonly caused by mutations in amyloid precursor protein (APP) or genes involved in the processing of APP including the presenilins (e.g. PSEN1 or PSEN2). In general, mouse models relevant to EOAD recapitulate amyloidosis, show only limited amounts of NFTs and neuronal cell dysfunction and low but significant levels of seizure susceptibility. To investigate the effect of genetic background on these phenotypes, we generated APPswe and PSEN1de9 transgenic mice on the seizure prone inbred strain background, DBA/2J. Previous studies show that the DBA/2J genetic background modifies plaque deposition in the presence of mutant APP but the impact of PSEN1de9 has not been tested. Our study shows that DBA/2J.APPswePSEN1de9 mice are significantly more prone to premature lethality, likely to due to lethal seizures, compared to B6.APPswePSEN1de9 mice-70% of DBA/2J.APPswePSEN1de9 mice die between 2-3 months of age. Of the DBA/2J.APPswePSEN1de9 mice that survived to 6 months of age, plaque deposition was greatly reduced compared to age-matched B6.APPswePSEN1de9 mice. The reduction in plaque deposition appears to be independent of microglia numbers, reactive astrocytosis and complement C5 activity.
The Jackson Laboratory, Bar Harbor, Maine, United States of America.
Harriet M
HM
Jackson
The Jackson Laboratory, Bar Harbor, Maine, United States of America.
Kristen D
KD
Onos
The Jackson Laboratory, Bar Harbor, Maine, United States of America.
Keating W
KW
Pepper
The Jackson Laboratory, Bar Harbor, Maine, United States of America; Sackler School of Medicine, Tufts University, Boston, United States of America.
Leah C
LC
Graham
The Jackson Laboratory, Bar Harbor, Maine, United States of America.
Ellen C
EC
Akeson
The Jackson Laboratory, Bar Harbor, Maine, United States of America.
Candice
C
Byers
The Jackson Laboratory, Bar Harbor, Maine, United States of America.
Laura G
LG
Reinholdt
The Jackson Laboratory, Bar Harbor, Maine, United States of America.
Wayne N
WN
Frankel
The Jackson Laboratory, Bar Harbor, Maine, United States of America; Sackler School of Medicine, Tufts University, Boston, United States of America.
Gareth R
GR
Howell
D000375:Aging / Q000473:pathology; D000544:Alzheimer Disease / Q000150:complications* / Q000473:pathology*; D000682:Amyloid / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D033481:Chromosomes, Mammalian / Q000235:genetics; D003182:Complement C5 / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004198:Disease Susceptibility; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology; D016254:Mutagenesis, Insertional; D009474:Neurons / Q000473:pathology; D010641:Phenotype; D058225:Plaque, Amyloid / Q000473:pathology; D053763:Presenilins / Q000378:metabolism; D012640:Seizures / Q000150:complications* / Q000473:pathology*; D019076:Transgenes
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D003182:Complement C5; D053763:Presenilins