Early hippocampal hyperexcitability in PS2APP mice: role of mutant PS2 and APP

Abstract

Alterations of brain network activity are observable in Alzheimer's disease (AD) together with the occurrence of mild cognitive impairment, before overt pathology. However, in humans as well in AD mouse models, identification of early biomarkers of network dysfunction is still at its beginning. We performed in vivo recordings of local field potential activity in the dentate gyrus of PS2APP mice expressing the human amyloid precursor protein (APP) Swedish mutation and the presenilin-2 (PS2) N141I. From a frequency-domain analysis, we uncovered network hyper-synchronicity as early as 3 months, when intracellular accumulation of amyloid beta was also observable. In addition, at 6 months of age, we identified network hyperactivity in the beta/gamma frequency bands, along with increased theta-beta and theta-gamma phase-amplitude cross-frequency coupling, in coincidence with the histopathological traits of the disease. Although hyperactivity and hypersynchronicity were respectively detected in mice expressing the PS2-N141I or the APP Swedish mutant alone, the increase in cross-frequency coupling specifically characterized the 6-month-old PS2APP mice, just before the surge of the cognitive decline.

Blood-brain barrier dysfunction in aging induces hyper-activation of TGF-beta signaling and chronic yet reversible neural dysfunction

“…We found that BBB dysfunction and consequent albumin extravasation appears as early as middle age, placing it among the earliest known hallmarks of the aging brain. Consistent with our findings, relatively subtle changes in neural and synaptic function have been widely observed in humans and other mammals as one of the first signs of neurological aging (64)(65)(66)(67), and these changes in neurotransmission are associated with hippocampal hyperexcitability that is thought to be one of the earliest events in the progression of mild cognitive impairment (43,44,68). However, the regulatory pathways that may trigger or control these changes are unknown.…”

“…Based on the finding that BBB dysfunction and TGFβ signaling causes hyperexcitability after head injury (22,24,(26)(27)(28)39), we hypothesized that similar hyperexcitability may be triggered by BBB decline and contribute to cognitive impairment in aging mice. Indeed, hippocampal hyperexcitability is an early biomarker of mild cognitive impairment in humans that precedes progression to AD (42,43), and is also an early marker of disease progression in rodent AD models (44,45). Thus, we used the pentylenetetrazol (PTZ) seizure assay to investigate the time course for onset and progression of hyperexcitability in aging mice.…”

Dampened Slow Oscillation Connectivity Anticipates Amyloid Deposition in the PS2APP Mouse Model of Alzheimer’s Disease

“…In particular, by using electrophysiological approaches, both in vitro and in vivo, previous studies pointed to an excitatory/inhibitory imbalance in the hippocampus leading to an altered ratio between hyperactive and silent neurons [10,11]. Both hyper-excitability and hyper-synchronicity characterize the early stages in AD mouse models [12][13][14][15][16][17], as well as in patients [18,19].…”

“…The spontaneous electrical activity of WT mice was thus compared to that of the double tg B6.152H mice, which express both the human APP-KM670/671NL (Swedish) and the PS2-N141I mutations, and show the first appearance of plaques and gliosis in the cortex and HPF at six months of age [26,27]. These mice have been studied by Positron Emission Tomography (PET) [28,29] and Magnetic Resonance Imaging (MRI) [30], as well as through pharmacological, electrophysiological, and Ca 2+ imaging approaches [12,31,32]. To identify the differences related to either the initial accumulation of Aβ or the deposition of plaques, we used mouse cohorts of three and six months of age, corresponding, respectively, to either the absence or presence of plaques and gliosis in B6.152H mice [12,26].…”

Coffee polyphenols prevent cognitive dysfunction and suppress amyloid β plaques in APP/PS2 transgenic mouse

“…Aβ deposition is observed in APP/PS2 mice from 2 to 3 months of age and it increases with age; cognitive function decreases after 4–5 months of age [17, 18]. Fontata and colleagues reported that synaptic excitability of the hippocampus changes from 3 months of age in APP/PS2 mice [26]. In addition, the increase in Aβ deposition in humans begins 15–20 years before AD onset [6].…”