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

Abstract

To fight Alzheimer’s disease (AD), we should know when, where, and how brain network dysfunctions initiate. In AD mouse models, relevant information can be derived from brain electrical activity. With a multi-site linear probe, we recorded local field potentials simultaneously at the posterior-parietal cortex and hippocampus of wild-type and double transgenic AD mice, under anesthesia. We focused on PS2APP (B6.152H) mice carrying both presenilin-2 (PS2) and amyloid precursor protein (APP) mutations, at three and six months of age, before and after plaque deposition respectively. To highlight defects linked to either the PS2 or APP mutation, we included in the analysis age-matched PS2.30H and APP-Swedish mice, carrying each of the mutations individually. Our study also included PSEN2−/− mice. At three months, only predeposition B6.152H mice show a reduction in the functional connectivity of slow oscillations (SO) and in the power ratio between SO and delta waves. At six months, plaque-seeding B6.152H mice undergo a worsening of the low/high frequency power imbalance and show a massive loss of cortico-hippocampal phase-amplitude coupling (PAC) between SO and higher frequencies, a feature shared with amyloid-free PS2.30H mice. We conclude that the PS2 mutation is sufficient to impair SO PAC and accelerate network dysfunctions in amyloid-accumulating mice.

Presenilin-2 and Calcium Handling: Molecules, Organelles, Cells and Brain Networks

“…Unique features of 2TG mice help to mark the progression of Aβ accumulation and deposition—loss of functional connectivity in the slow-wave range marks the onset of Aβ accumulation, similarly to what reported in PS1-based AD mice [ 106 ], whereas low/high power imbalances characterize Aβ deposition in plaque-seeding mice [ 108 ]. Since Aβ42 oligomers are associated with Ca 2+ homeostasis dysregulation [ 110 , 111 , 112 , 113 ], it is tempting to speculate that, in 2TG mice, Ca 2+ handling alterations, due to PS2-N141I, sum up or synergize with defects linked to Aβ accumulation.…”

“…We used this approach to study brain rhythmicity at the cortical and hippocampal levels. In both TG and 2TG mice, the total power, which mostly reflects spontaneous activity in the low frequency range (0.1–5 Hz), is reduced, particularly at the hippocampal level, suggesting that the PS2 mutant by itself alters the brain electrical activity [ 108 ].…”

“…Another interesting feature shared by both TG and 2TG mice is the disruption of cortico-hippocampal oscillation coupling ( Figure 2 , [ 108 ]). The phenomenon, also known as phase-amplitude coupling (PAC), occurs when the phase of slower rhythms influences the amplitude of faster ones, and it has been found to be involved in memory consolidation and information transfer [ 105 , 109 ].…”

“…At the brain circuit level, the FAD-linked PS2-N141I mutant increases excitability [ 54 , 100 ] and disrupts the coupling of cortical slow-waves to hippocampal fast gamma frequencies [ 108 ]. Altogether, these findings are consistent with the high frequency of seizures and behavioral changes found in both FAD-PS2-N141I patients [ 1 ] and other mouse models expressing PS2-N141I [ 114 , 115 ].…”

Intracellular Calcium Dysregulation by the Alzheimer’s Disease-Linked Protein Presenilin 2

“…Moreover, in primary neurons from B6.152H tg mice, cell bioenergetics was also significantly affected [178]. Finally, the Ca 2+ hyperactivity described in both FAD-PS2 mouse models likely contributes to the hyper-excitability found at the brain network level in adult, anesthetized animals, in the presence or absence of Aβ accumulation [163,179,180].…”