Pathological and neurophysiological outcomes of seeding human-derived tau pathology in the APP-KI NL-G-F and NL-NL mouse models of Alzheimer’s Disease

Abstract

The two main histopathological hallmarks that characterize Alzheimer’s Disease are the presence of amyloid plaques and neurofibrillary tangles. One of the current approaches to studying the consequences of amyloid pathology relies on the usage of transgenic animal models that incorporate the mutant humanized form of the amyloid precursor protein (hAPP), with animal models progressively developing amyloid pathology as they age. However, these mice models generally overexpress the hAPP protein to facilitate the development of amyloid pathology, which has been suggested to elicit pathological and neuropathological changes unrelated to amyloid pathology. In this current study, we characterized APP knock-in (APP-KI) animals, that do not overexpress hAPP but still develop amyloid pathology to understand the influence of protein overexpression. We also induced tau pathology via human-derived tau seeding material to understand the neurophysiological effects of amyloid and tau pathology. We report that tau-seeded APP-KI animals progressively develop tau pathology, exacerbated by the presence of amyloid pathology. Interestingly, older amyloid-bearing, tau-seeded animals exhibited more amyloid pathology in the entorhinal area, isocortex and hippocampus, but not thalamus, which appeared to correlate with impairments in gamma oscillations before seeding. Tau-seeded animals also featured immediate deficits in power spectra values and phase-amplitude indices in the hippocampus after seeding, with gamma power spectra deficits persisting in younger animals. Both deficits in hippocampal phase-amplitude coupling and gamma power differentiate tau-seeded, amyloid-positive animals from buffer controls. Based on our results, impairments in gamma oscillations appear to be strongly associated with the presence and development of amyloid and tau pathology, and may also be an indicator of neuropathology, network dysfunction, and even potential disposition to the future development of amyloid pathology.

Revealing the combined roles of Aβ and tau in Alzheimer’s disease via a pathophysiological activity decoder

“…Our findings confirm previous observations 3,11,15,16,19,20 and cast new light on microscopical pathological processes that are inaccessible to traditional neuroimaging methods.…”

“…Our findings confirm previous observations 3, 11, 15, 16, 19, 20 and cast new light on microscopical pathological processes that are inaccessible to traditional neuroimaging methods. Through considering the influence of multiple pathophysiological factors, we have retrieved the AD electrophysiological hallmark (enhancement of theta band activity together with alpha decreases, as disease progresses 10, 11 ) from BOLD signals.…”

“…For example, the hypersynchronous epileptiform activity observed in over 60% of AD cases 19 may be generated by surrounding Aβ and/or tau deposition increasing network hyperactivity 19,20 .…”

“…In-vivo animal experiments indicate that both Aβ and tau pathologies synergistically interact to impair neuronal circuits 16 . For example, the hypersynchronous epileptiform activity observed in over 60% of AD cases 19 may be generated by surrounding Aβ and/or tau deposition increasing network hyperactivity 19, 20 . In an apparent feedback loop, endogenous neuronal activity, in turn, regulates Aβ aggregation, in both animal models and computational simulations 21, 22 .…”

Transcriptomic signatures of Aβ- and tau-induced neuronal dysfunction reveal inflammatory processes at the core of Alzheimer’s disease pathophysiology

“…PET-measured Aβ and tau aggregation in the brain serve to predict cognitive decline (Chandra et al, 2019). In-vivo animal experiments and modeling approaches suggest that Aβ and tau also synergistically interact to impair neuronal (Maestú et al, 2021; Targa Dias Anastacio et al, 2022; van Nifterick et al, 2022), with Aβ and tau pathologies likely prompting brain network hyperactivity as the disease progresses (Busche & Hyman, 2020; Tok et al, 2022; Vossel et al, 2017). Although these effects are consistent across the literature, limitations to concurrently measure neuronal activity alterations, pathological severity, and molecular profiles in the living human brain represent a major obstacle towards clarifying AD mechanisms (Gabitto et al, n.d.; Iturria-Medina et al, 2022; Maestú et al, 2021; Nandi et al, 2022).…”