Emergence of a seizure phenotype in aged apolipoprotein epsilon 4 targeted replacement mice.
The apolipoprotein ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and is associated with earlier age of onset. The incidence of spontaneous seizures has been reported to be increased in sporadic AD as well as in the early onset autosomal dominant forms of AD. We now report the emergence of a seizure phenotype in aged apolipoprotein E4 (apoE4) targeted replacement (TR) mice but not in age-matched apoE2 TR or apoE3 TR mice. Tonic-clonic seizures developed spontaneously after 5 months of age in apoE4 TR mice and are triggered by mild stress. Female mice had increased seizure penetrance compared to male mice, but had slightly reduced overall seizure severity. The majority of seizures were characterized by head and neck jerks, but 25% of aged apoE4 TR mice had more severe tonic-clonic seizures which occasionally progressed to tonic extension and death. Aged apoE4 TR mice progressed through pentylenetetrazol-induced seizure stages more rapidly than did apoE3 TR and apoE2 TR mice. Electroencephalographic (EEG) recordings revealed more frequent bursts of synchronous theta activity in the hippocampus of apoE4 TR mice than in apoE2 TR or apoE3 TR mice. Cortical EEG recordings also revealed sharp spikes and other abnormalities in apoE4 TR mice. Taken together, these findings demonstrate the emergence of an age-dependent seizure phenotype in old apoE4 TR mice in the absence of human amyloid-β peptide (Aβ) overexpression, suggesting increased central nervous system neural network excitability.
Neuroscience Discovery, Eli Lilly and Co., Indianapolis, IN 46285, USA. jeshnt@gmail.com
Jesse M
JM
Hunter
John R
JR
Cirrito
Jessica L
JL
Restivo
Robert D
RD
Kinley
Patrick M
PM
Sullivan
David M
DM
Holtzman
Deanna
D
Koger
Cynthia
C
Delong
Suizhen
S
Lin
Lingzhi
L
Zhao
Feng
F
Liu
Kelly
K
Bales
Steven M
SM
Paul
D000375:Aging / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism; D000818:Animals; D053327:Apolipoprotein E4 / Q000097:blood / Q000235:genetics*; D001522:Behavior, Animal / Q000502:physiology; D015415:Biomarkers; D001835:Body Weight; D002540:Cerebral Cortex / Q000503:physiopathology; D003292:Convulsants; D004569:Electroencephalography; D004797:Enzyme-Linked Immunosorbent Assay; D006624:Hippocampus / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology; D010433:Pentylenetetrazole; D010641:Phenotype; D012640:Seizures / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology*
D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D015415:Biomarkers; D003292:Convulsants; D010433:Pentylenetetrazole