Abstract
IntroductionIn Alzheimer's disease (AD), pathologic amyloid-beta (Aβ) is synaptotoxic and impairs neuronal function at the microscale, influencing brain networks at the macroscale before Aβ deposition. The latter can be detected noninvasively, in vivo, using resting-state functional MRI (rsfMRI), a technique used to assess brain functional connectivity (FC). MethodsRsfMRI was performed longitudinally in TG2576 and PDAPP mice, starting before Aβ deposition to determine the earliest FC changes. Additionally, the role of pathologic Aβ on early FC alterations was investigated by treating TG2576 mice with the 3D6 anti-Aβ-antibody. ResultsBoth transgenic models showed hypersynchronized FC before Aβ deposition and hyposynchronized FC at later stages. Early anti-Aβ treatment in TG2576 mice prevented hypersynchronous FC and the associated synaptic impairments and excitatory/inhibitory disbalances. DiscussionHypersynchrony of FC may be used as a new noninvasive read out of early AD and can be recovered by anti-Aβ treatment, encouraging preventive treatment strategies in familial AD.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, characterized by deficits in learning, memory, FLA 5.4.0 DTD JALZ2159_proof 5 May 2016 12:53 pm ceD
BOLD Functional connectivity (FC) was assessed in TG2576 mice before (3, 5 and 8 months) and after Ab plaque deposition (14 and 18 months)
Starting from 8 until 18 months of age, BOLD FC decreased in TG2576 mice compared to wild-type mice
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, characterized by deficits in learning, memory, FLA 5.4.0 DTD JALZ2159_proof 5 May 2016 12:53 pm ceD. Several transgenic mouse models of amyloidosis show cognitive dysfunctions and impaired synaptic functioning before the manifestation of Ab plaques [5,6,7,8,9,10,11] supporting a destructive role of soluble Ab on neurologic processes that underlie learning and memory. Synaptic dysfunction elicited by soluble Ab leads to impaired communication between brain regions, resulting in deficits of neuronal networks which could be expressed as cognitive disturbances [4,12]. The noninvasive detection of such network alterations would allow elucidating the spatiotemporal relation between amyloid pathology and functional impairments and provide a tool for early diagnosis. Alterations at the neuronal network level can be detected noninvasively using resting-state functional magnetic resonance imaging (rsfMRI). Functional connectivity (FC) is defined as the temporal correlation of BOLD fluctuations between spatially distinct brain regions [13]
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