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

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 aim...

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Published in:	Alzheimer's research & therapy Vol. 14; no. 1; p. 148
Main Authors:	van den Berg, Monica, Adhikari, Mohit H, Verschuuren, Marlies, Pintelon, Isabel, Vasilkovska, Tamara, Van Audekerke, Johan, Missault, Stephan, Heymans, Loran, Ponsaerts, Peter, De Vos, Winnok H, Van der Linden, Annemie, Keliris, Georgios A, Verhoye, Marleen
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 10-10-2022 BioMed Central BMC
Subjects:	Alzheimer Disease - pathology Alzheimer's disease Amyloid beta-Peptides Animal cognition Animals Basal forebrain Basal Forebrain - diagnostic imaging Cholinergic Agents Cognitive ability Dementia Development and progression Disease Models, Animal Evaluation gamma-Aminobutyric Acid Gliosis Network dysfunction Network switching Pathology Plaque, Amyloid Rats Rats, Inbred F344 Rats, Transgenic Resting state functional MRI Risk factors Software Synaptic dysfunction Ventilators Belgium United States > US Germany Gliosis Network dysfunction Resting state functional MRI Alzheimer’s disease Synaptic dysfunction Basal forebrain Amyloid Quasi-periodic patterns
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Summary:	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. 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 a 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 pre-plaque stage was absent at the early-plaque stage. Moreover, altered excitatory/inhibitory balance was observed in cortical regions belonging to the default mode-like network. 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. 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, possibly 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1758-9193 1758-9193
DOI:	10.1186/s13195-022-01089-2