RESUMO
Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD), but the mechanism by which it causes cognitive decline is unclear. In knockin (KI) mice, human apoE4 causes age-dependent learning and memory impairments and degeneration of GABAergic interneurons in the hippocampal dentate gyrus. Here we report two functional apoE4-KI phenotypes involving sharp-wave ripples (SWRs), hippocampal network events critical for memory processes. Aged apoE4-KI mice had fewer SWRs than apoE3-KI mice and significantly reduced slow gamma activity during SWRs. Elimination of apoE4 in GABAergic interneurons, which prevents learning and memory impairments, rescued SWR-associated slow gamma activity but not SWR abundance in aged mice. SWR abundance was reduced similarly in young and aged apoE4-KI mice; however, the full SWR-associated slow gamma deficit emerged only in aged apoE4-KI mice. These results suggest that progressive decline of interneuron-enabled slow gamma activity during SWRs critically contributes to apoE4-mediated learning and memory impairments. VIDEO ABSTRACT.
Assuntos
Apolipoproteína E4/metabolismo , Transtornos Cognitivos/metabolismo , Hipocampo/metabolismo , Interneurônios/metabolismo , Transtornos da Memória/metabolismo , Envelhecimento , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Apolipoproteína E4/genética , Transtornos Cognitivos/genética , Modelos Animais de Doenças , Técnicas de Introdução de Genes/métodos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/genética , Camundongos TransgênicosRESUMO
OBJECTIVE: To examine the validity of a novel caffeine intake questionnaire and to examine the effects of caffeine on sleep in college students. METHODS: One-week, ad libitum behavior of 50 university students (28 female, 22 male; aged 20.9 ± 1.78 years) was examined with sleep logs, wrist actigraphy, and a novel daily questionnaire assessing caffeine intake at different times of day. Saliva samples were collected for caffeine assessment (questionnaire validation) and DNA extraction, and for analysis of a single nucleotide polymorphism in the adenosine receptor 2A (ADORA2A) gene. RESULTS: The caffeine questionnaire was able to accurately predict salivary concentrations of caffeine (R(2) = 0.41, P<0.001). Estimations of integrated salivary caffeine concentration during sleep were correlated with wake after sleep onset (WASO) most strongly in morning-type individuals (R(2) = 0.49; P<0.001, ANOVA), less so in intermediate chronotypes (R(2) = 0.16; P<0.001, ANOVA), and not significantly in evening-types (R(2) = 0.00098; P = 0.13, ANOVA). Using multivariate modeling methods we found that the ADORA2A genotype did not moderate the effects of caffeine on WASO, but did independently alter WASO such that those with the CC genotype had nearly three-times as much WASO as those with CT or TT. CONCLUSIONS: Our questionnaire was able to accurately predict salivary caffeine concentrations and helped to describe a novel relationship between the effects of caffeine on sleep and genotype and chronotype.
