Pathological Alterations Induced by intraneuronal in Alzheimer’s Disease

Die Alzheimer Demenz (AD) ist neuropathologisch durch das Auftreten von β-Amyloid (Aβ) und Neurofibrillenbündeln, die aus hyperphosphoryliertem Tau Protein bestehen, charakterisiert. Die Ablagerung von Aβ Peptiden wird als ursächlicher pathologischer Mechanismus betrachtet, da familiär auftretende Mutationen in Proteinen die in der Aβ?Kaskade eine Rolle spielen unweigerlich zur AD führen. Im Gegensatz dazu führen Mutationen im Tau Protein zu Fronto-Temporaler Demenz. Die Amyloid-Hypothese geht davon aus, dass die Akkumulation von Aβ42 ursächlich für die Beeinträchtigung von Nervenzellen und Synapsen ist und letztendlich zu Verhaltensdefiziten führt. Für viele Jahre galt das Hauptaugenmerk der Amyloid-Hypothese dem Auftreten extrazellulärer Aβ-Plaques. In einer Vielzahl von Mausmodellen, die auf familiären Mutationen basieren, konnte die Ablagerung dieser Plaques erfolgreich nachgebildet werden, allerdings traten nur schwache Verhaltensdefizite und kein deutlicher Nervenzellverlust auf. Extrazelluläre Plaque-Pathologie korreliert darüber hinaus nicht mit bei AD Patienten beobachteten kognitiven Defiziten und kommt auch bei Kontrollpatienten vor, die keine Anzeichen einer Demenz aufweisen. Kürzlich wurde eine modifizierte Amyloid-Hypothese vorgestellt, in der frühen intrazellulären Aβ-Akkumulationen, im Gegensatz zu extrazellulären Aβ Plaques eine zentrale Rolle in der pathologischen Kaskade zukommt. Allerdings ist das Vorkommen intrazellulärer Aβ Peptide bei der AD noch Gegenstand wissenschaftlicher Diskussion. Die vorliegende Arbeit untersucht das Vorkommen intrazellulärer Aβ Peptide im Hirngewebe von Alzheimer Patienten, sowie deren Rolle im Gegensatz zu extrazellulärer Plaquepathologie in transgenen Mausmodellen der AD. Nervenzellverlust, axonale Pathologie und funktionelle Defizite im Hinblick auf die Regulation der Expression früher Gene (immediate early genes, IEG) werden dabei besonders berücksichtigt. Im Hinblick auf pathologische Veränderungen bestätigt die vorliegende Arbeit die modifizierte Amyloid-Hypothese. Die Ergebnisse unterstützen die Rolle von intraneuronalem Aβ als früher Auslöser der pathologischen Kaskade und zeigen einen deutlichen Zusammenhang zu axonaler Degeneration und Nervenzellverlust auf. Im Gegensatz dazu scheinen extrazelluläre Plaques eher an funktionellen Defiziten wie etwa der Induktion von IEGs bei neuronaler Aktivität, nicht aber am Nervenzellverlust beteiligt zu sein. Durch eine Optimierung des immunhistochemischen Färbeprotokolls konnte eine deutliche Färbung intraneuronaler Aβ Peptide in Nervenzellen des Hippokampus im Hirngewebe von AD Patienten nachgewiesen werden. Darüber hinaus wurde ein Zusammenhang zwischen der Präsenz des ApoE4 Allels, einem bekannten Risikofaktor für die AD, und intraneuronalem Aβ gefunden, was die wichtige Rolle von Aβ Peptiden innerhalb von Nervenzellen bei der Pathologie der AD unterstreicht

Ongoing electroencephalographic activity associated with cortical arousal in trangenic pdapp mice

Background: It has been shown that theta (6-10 Hz) and delta (1-6 Hz) ongoing electroencephalographic (EEG) rhythms revealed variations in the cortical arousal in C57 Wild Type (WT) mice during cage exploration (active condition) compared to awake quiet behavior (passive condition; IMI PharmaCog project, www.pharmacog.eu). Objective: The objective was to test if these EEG rhythms might be abnormal in old PDAPP mice modeling Alzheimer’s disease (AD) with a hAPP Indiana V717F mutation (They show abnormal neural transmission, cognitive deficits, and brain accumulation of Aβ1-42). Methods: Ongoing EEG rhythms were recorded by a frontoparietal bipolar channel in 15 PDAPP and 23 WT C57 male mice (mean age of 22.8 months ±0.4 and 0.3 standard error, respectively). EEG absolute power (density) was calculated. Frequency and amplitude of individual delta and theta frequency (IDF and ITF) peaks were considered during passive and active states in the wakefulness. Results: Compared with the WT group, the PDAPP group showed higher frequency of the IDF during the passive condition and lower frequency of the ITF during the active state. Furthermore, the WT but not PDAPP group showed significant changes in the frontoparietal EEG power (IDF, ITF) during active over passive state. Conclusion: PDAPP mice were characterized by less changes in the brain arousal during an active state as revealed by frontoparietal EEG rhythms. Future studies will have to cross-validate the present results on large animal groups, clarify the neurophysiological underpinning of the effect, and test if the disease modifying drugs against AD amyloidosis normalize those candiate EEG biomarkers in PDAPP mic

On-going electroencephalographic rhythms related to cortical arousal in wild-type mice: the effect of aging

Resting state electroencephalographic (EEG) rhythms reflect the fluctuation of cortical arousal and vigilance in a typical clinical setting, namely the EEG recording for few minutes with eyes closed (i.e., passive condition) and eyes open (i.e., active condition). Can this procedure be back-translated to C57 (wild type) mice for aging studies? On-going EEG rhythms were recorded from a frontoparietal bipolar channel in 85 (19 females) C57 mice. Male mice were subdivided into 3 groups: 25 young (4.5-6 months), 18 middle-aged (12-15 months), and 23 old (20-24 months) mice to test the effect of aging. EEG power density was compared between short periods (about 5 minutes) of awake quiet behavior (passive) and dynamic exploration of the cage (active). Compared with the passive condition, the active condition induced decreased EEG power at 1-2 Hz and increased EEG power at 6-10 Hz in the group of 85 mice. Concerning the aging effects, the passive condition showed higher EEG power at 1-2 Hz in the old group than that in the others. Furthermore, the active condition exhibited a maximum EEG power at 6-8 Hz in the former group and 8-10 Hz in the latter. In the present conditions, delta and theta EEG rhythms reflected changes in cortical arousal and vigilance in freely behaving C57 mice across aging. These changes resemble the so-called slowing of resting state EEG rhythms observed in humans across physiological and pathological aging. The present EEG procedures may be used to enhance preclinical phases of drug discovery in mice for understanding the neurophysiological effects of new compounds against brain aging

Ongoing electroencephalographic rhythms related to exploratory movements in\ua0transgenic TASTPM mice

Background: The European PharmaCog study (http://www.pharmacog.org) has reported a reduction in delta (1-6 Hz) electroencephalographic (EEG) power (density) during cage exploration (active condition) compared with quiet wakefulness (passive condition) in PDAPP mice (hAPP Indiana V717F mutation) modeling Alzheimer's disease (AD) amyloidosis and cognitive deficits. Objective: Here, we tested the reproducibility of that evidence in TASTPM mice (double mutation in APP KM670/671NL and PSEN1 M146V), which develop brain amyloidosis and cognitive deficits over aging. The reliability of that evidence was examined in four research centers of the PharmaCog study. Methods: Ongoing EEG rhythms were recorded from a frontoparietal bipolar channel in 29 TASTPM and 58 matched "wild type" C57 mice (range of age: 12-24 months). Normalized EEG power was calculated. Frequency and amplitude of individual delta and theta frequency (IDF and ITF) peaks were considered during the passive and active conditions. Results: Compared with the "wild type" group, the TASTPM group showed a significantly lower reduction in IDF power during the active over the passive condition (p < 0.05). This effect was observed in 3 out of 4 EEG recording units. Conclusion: TASTPM mice were characterized by "poor reactivity" of delta EEG rhythms during the cage exploration in line with previous evidence in PDAPP mice. The reliability of that result across the centers was moderate, thus unveiling pros and cons of multicenter preclinical EEG trials in TASTPM mice useful for planning future studies

Effects of pharmacological agents, sleep deprivation, hypoxia and transcranial magnetic stimulation on electroencephalographic rhythms in rodents: towards translational challenge models for drug discovery in Alzheimer's disease

Different kinds of challenge can alter spontaneous ongoing electroencephalographic (EEG) rhythms in animal models, thus providing paradigms to evaluate treatment effects in drug discovery. The effects of challenges represented by pharmacological agents, hypoxia, sleep deprivation and transcranial magnetic stimulation (TMS) on EEG rhythms are here reviewed to build a knowledge platform for innovative translational models for drug discovery in Alzheimer's disease (AD). It has been reported that antagonists of cholinergic neurotransmission cause synchronisation of spontaneous ongoing EEG rhythms in terms of enhanced power of EEG low frequencies and decreased power of EEG high frequencies. Acetylcholinesterase inhibitors and serotonergic drugs may restore a normal pattern of EEG desynchronisation. Sleep deprivation and hypoxia challenges have also been reported to elicit abnormal synchronisation of spontaneous ongoing EEG rhythms in rodents. The feasibility and reproducibility of TMS have been demonstrated in rodents but information on a consistent modulation of EEG after TMS manipulation is very limited. Transgenic mice over-expressing human amyloid precursor protein complementary DNAs (cDNAs) harbouring the 'Swedish' mutation and PS-1 cDNAs harbouring the A264E mutation, which recapitulate some of the pathological features of AD, exhibit alterations of spontaneous ongoing EEG rhythms at several low and high frequencies. This does not appear, however, to be a consequence of beta-amyloid deposition in the brain. The present review provides a critical evaluation of changes of spontaneous ongoing EEG rhythms due to the experimental manipulations described above, in order to stimulate the promote more adherent models fitting dynamics in humans