Abstract
Objective. In this exploratory study, we tested whether electroencephalographic (EEG) rhythms may reflect the effects of a chronic administration (4 weeks) of an anti-amyloid β-site amyloid precursor protein (APP) cleaving enzyme 1 inhibitor (BACE-1; ER-901356; Eisai Co., Ltd., Tokyo, Japan) in TASTPM (double mutation in APP KM670/671NL and PSEN1 M146V) producing Alzheimer’s disease (AD) amyloid neuropathology as compared to wild type (WT) mice. Methods. Ongoing EEG rhythms were recorded from a bipolar frontoparietal and two monopolar frontomedial (prelimbic) and hippocampal channels in 11 WT Vehicle, 10 WT BACE-1, 10 TASTPM Vehicle, and 11 TASTPM BACE-1 mice (males; aged 8/9 months old at the beginning of treatment). Normalized EEG power (density) was compared between the first day (Day 0) and after 4 weeks (Week 4) of the BACE-1 inhibitor (10 mg/Kg) or vehicle administration in the 4 mouse groups. Frequency and magnitude of individual EEG delta and theta frequency peaks (IDF and ITF) were considered during animal conditions of behaviorally passive and active wakefulness. Cognitive status was not tested. Results. Compared with the WT group, the TASTPM group generally showed a significantly lower reactivity in frontoparietal ITF power during the active over the passive condition (p < 0.05). Notably, there was no other statistically significant effect (e.g., additional electrodes, recording time, and BACE-1 inhibitor). Conclusions. The above EEG biomarkers reflected differences between the WT and TASTPM groups, but no BACE-1 inhibitor effect. The results suggest an enhanced experimental design with the use of younger mice, longer drug administrations, an effective control drug, and neuropathological amyloid markers.
Highlights
Alzheimer’s disease (AD) is the most diffuse progressive neurodegenerative disorder that affects aging [1,2,3])
No stpaatsissitviec)a, ltlryeatsmigenntif(iVceahnictleefafnedctBAwCaEs-1o;binsdeerpveenddeinnt vthareiarbeles)u, latnsdotifmtehe(DAayN0OanVdAWeteekst4in) fgactthores power ratio betw(pee>n0.I0T5)F. and IDF (ITF/IDF) at the frontomedial prelimbic and hippocampal channels as dependen2t.5v. aCroinatbrolleAs nianlyrsieslation to the group (WT and TASTPM; independent variable), condition, treatment (Vehicle and BACE-1; independent variable), and time (Day 0 and factorTsh(epm>a0in.0r5es)u. lts lasting four weeks did of the present study showed that the BACE-1 inhibitor ER-901356 treatment not affect EEG rhythms in wild type (WT) and TASTPM mice (PS1 and amyloid precursor protein (APP) mutations)
We tested whether ongoing EEG rhythms at delta and theta frequencies may be able to reflect neurophysiological effects of a chronic treatment affecting insoluble amyloid β in the brain in an AD mouse model, i.e., the TASTPM mice
Summary
Alzheimer’s disease (AD) is the most diffuse progressive neurodegenerative disorder that affects aging [1,2,3]). A wealth of studies has documented abnormal EEG activities at delta and theta rhythms (i.e., hyper-synchronous activities) in APP- and PS1-mutated transgenic models showing progressive amyloidosis in the brain: (1) mice with mutations in the APP gene showed abnormal ongoing EEG rhythms [16]. (2) Mice carrying mutated human APP Swedish and PS1 genes showing fibrillogenic Aβ1-42 and amyloid plaques exhibited reduced theta (absolute power) and enhanced beta and gamma (absolute power) EEG rhythms recorded in wakefulness; those changes did not dependent on Aβ1-42 deposits as they did not progress over aging from 9 months of age [17]. (6) Triple transgenic mice (i.e., 3×Tg and PLB1 triple) over controls were characterized by a decrease of theta EEG rhythms during wakefulness or cognitive tasks [21,22] and an increase of delta EEG rhythms during wakefulness and REM sleep [20]. APP but not PS1 single mutant mice, had similar alterations in theta, beta, and gamma EEG rhythms, while APP/PS1 (but not APP single-mutant) mice had high insoluble Aβ1-42/40 levels and core brain amyloid plaques at 13 months of age [17]. (3) APP Swedish and PS1 mutant mice showed increased EEG (absolute power) rhythms at a large frequency band beyond delta rhythms [18,19]. (4) The second generation of AD mouse models as triple transgenic mice (i.e., triple transgenic mice express low levels of mutant human APP, tau, and presenilin-1) presented abnormal EEG rhythms [20,21,22]. (5) The same was true in humanized mice containing functional human cells or tissues [23,24]. (6) Triple transgenic mice (i.e., 3×Tg and PLB1 triple) over controls were characterized by a decrease of theta EEG rhythms during wakefulness or cognitive tasks [21,22] and an increase of delta EEG rhythms during wakefulness and REM sleep [20]. (7) Triple-transgenic AD mice challenged with the potassium channel blocker 4-aminopyridine showed reduced theta EEG rhythms compared with 4-aminopyridine-treated control mice [22]. (8) In rodents, abnormalities in delta EEG rhythms were related to impairments in long-term and short-term hippocampal plasticity and cognitive deficits in recognition memory and spatial learning [20]. (9) As compared to mice humanized to apolipoprotein APOE3, mice humanized to APOE4 showed abnormal beta EEG rhythms during olfactory tasks [25]. (10) In transgenic mice, the activation of basal forebrain cholinergic neurons, traced by humanized Renilla green fluorescent protein (hrGFP), significantly and lastingly decreased the delta EEG rhythms, produced low-delta non-rapid eye movement sleep, and slightly increased wakefulness, whereas the inhibition of basal forebrain cholinergic neurons significantly increased delta EEG rhythms and slightly decreased wakefulness [24]
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