Multimodal Imaging in Rat Model Recapitulates Alzheimer's Disease Biomarkers Abnormalities

Abstract

Imaging biomarkers are frequently proposed as endpoints for clinical trials targeting brain amyloidosis in Alzheimer's disease (AD); however, the specific impact of amyloid-β (Aβ) aggregation on biomarker abnormalities remains elusive in AD. Using the McGill-R-Thy1-APP transgenic rat as a model of selective Aβ pathology, we characterized the longitudinal progression of abnormalities in biomarkers commonly used in AD research. Middle-aged (9–11 months) transgenic animals (both male and female) displayed mild spatial memory impairments and disrupted cingulate network connectivity measured by resting-state fMRI, even in the absence of hypometabolism (measured with PET [18F]FDG) or detectable fibrillary amyloidosis (measured with PET [18F]NAV4694). At more advanced ages (16–19 months), cognitive deficits progressed in conjunction with resting connectivity abnormalities; furthermore, hypometabolism, Aβ plaque accumulation, reduction of CSF Aβ1-42 concentrations, and hippocampal atrophy (structural MRI) were detectable at this stage. The present results emphasize the early impact of Aβ on brain connectivity and support a framework in which persistent Aβ aggregation itself is sufficient to impose memory circuits dysfunction, which propagates to adjacent brain networks at later stages.SIGNIFICANCE STATEMENT The present study proposes a “back translation” of the Alzheimer pathological cascade concept from human to animals. We used the same set of Alzheimer imaging biomarkers typically used in large human cohorts and assessed their progression over time in a transgenic rat model, which allows for a finer spatial resolution not attainable with mice. Using this translational platform, we demonstrated that amyloid-β pathology recapitulates an Alzheimer-like profile of biomarker abnormalities even in the absence of other hallmarks of the disease such as neurofibrillary tangles and widespread neuronal losses.

Longitudinal Characterization and Biomarkers of Age and Sex Differences in the Decline of Spatial Memory

“…In humans, an increase in functional connectivity, which is initially associated with memory impairment, may predict further cognitive decline, reduced functional connectivity, and loss of brain volume with more advanced age (Reuter-Lorenz and Cappell, 2008;Wang et al, 2011;Staffaroni et al, 2018;Zheng et al, 2018). Similarly, in rodent models, impaired spatial episodic memory in middle-age may predict more severe cognitive deficits with advancing age (Foster, 2012) and increased dorsal hippocampus-RSC connectivity may foretell a future loss of hippocampus-RSC connectivity (Ash et al, 2016;Parent et al, 2017), and loss of hippocampal volume (Magalhaes et al, 2017;Reichel et al, 2017). For example, in a rat model of Alzheimer's disease, higher dorsal hippocampal connectivity in middle-age progressed to reduced dorsal hippocampus-RSC connectivity with age (Parent et al, 2017).…”

“…Similarly, in rodent models, impaired spatial episodic memory in middle-age may predict more severe cognitive deficits with advancing age (Foster, 2012) and increased dorsal hippocampus-RSC connectivity may foretell a future loss of hippocampus-RSC connectivity (Ash et al, 2016;Parent et al, 2017), and loss of hippocampal volume (Magalhaes et al, 2017;Reichel et al, 2017). For example, in a rat model of Alzheimer's disease, higher dorsal hippocampal connectivity in middle-age progressed to reduced dorsal hippocampus-RSC connectivity with age (Parent et al, 2017). Similarly, older rats characterized as impaired on a spatial reference memory task exhibited decreased dorsal hippocampus-RSC connectivity (Ash et al, 2016).…”

Neuroprotective Effects of Quercetin in Alzheimer’s Disease

“…Extensive fibrils along with activated microglia accumulated to form senile plaques, which lead to neuronal and synaptic loss. [2] Upstream regulating acetyl cholinesterase (AChE) enzyme promotes acetylcholine (Ach) degradation, resulting in neurotransmitter deficit, which leads to cognitive impairment. Amyloid precursor protein (APP), amyloid beta proteins (Aβ), neurofibrillary tangles (NFTs), acetylcholine (Ach), acetyl cholinesterase (AChE).…”

“…Alzheimer's disease (AD) contributes to 60-80% of total dementia cases, and it mostly affects elder people (65 years of age or older) [1]. The pathogenesis of AD is typically associated with the accumulation of amyloid-β (Aβ) aggregates and the hyperphosphorylation of tau proteins, leading to neurofibrillary tangles (NFTs) and synaptic dysfunction [2][3][4]. Around 35.6 million people worldwide are estimated to be affected with AD, with a prevalence rate of 4.6 million new cases each year.…”

“…Fibril Aβs upregulate oxidative stress, the inflammatory cascade, and caspase activation, which results into the hyperphosphorylation of the Tau protein to form neurofibrillary tangles(NFTs), and the ultimate result is neuronal cells loss. Extensive fibrils along with activated microglia accumulated to form senile plaques, which lead to neuronal and synaptic loss [2].…”