Altered basal forebrain function during whole-brain network activity at pre- and early-plaque stages of Alzheimer’s disease in TgF344-AD rats

Abstract

Background: Imbalanced synaptic transmission appears to be an early driver in Alzheimer’s Disease (AD) leading to brain network alterations. Early detection of altered synaptic transmission and insight into mechanisms causing early synaptic alterations would be valuable treatment strategies. This study aimed to investigate how whole-brain networks are influenced at pre- and early-plague stages of AD and if these manifestations are associated with concomitant cellular and synaptic deficits. Methods: To this end, we used an established AD rat model (TgF344-AD) and employed resting state functional MRI and quasi-periodic pattern (QPP) analysis, a method to detect recurrent spatiotemporal motifs of brain activity, in parallel with state-of-the-art immunohistochemistry in selected brain regions. Results: At the pre‑plaque stage, QPPs in TgF344-AD rats showed decreased activity of the basal forebrain (BFB) and the default-mode like network. Histological analyses revealed increased astrocyte abundance restricted to the BFB, in the absence of amyloid plaques, tauopathy and alterations in number of cholinergic, gaba-ergic and glutamatergic synapses. During the early-plaque stage, when mild amyloid-beta (Aβ) accumulation was observed in the cortex and hippocampus, QPPs in the TgF344-AD rats normalized suggesting the activation of compensatory mechanisms during this early disease progression period. Interestingly, astrogliosis observed in the BFB at the early-plaque stage was absent at the early-plaque stage. In wild-type rats, at both time-points, peak activity in the BFB preceded peak activity in other brain regions – indicating its modulatory role during QPPs. However, this pattern was eliminated in TgF344-AD suggesting that alterations in BFB-directed neuromodulation have a pronounced impact in network function in AD. Conclusions: This study demonstrates the value of rsfMRI and advanced network analysis methods to detect early alterations in BFB function in AD, which could aid early diagnosis and intervention in AD. Restoring the global synaptic transmission by modulating astrogliosis in the BFB might be a promising therapeutic strategy to restore brain network function and delay the onset of symptoms in AD.

Cerebrovascular Dysfunction in Alzheimer’s Disease and Transgenic Rodent Models

“…They were hyperactive in open field tests, indicating disinhibition associated with hippocampal or cortical injury. More recent studies have indicated that high levels of Aβ oligomers in the brain and spatial learning and memory impairments can be detected as early as 4-months in TgF344-AD rats [72][73][74].…”