Abstract
Improvements have been made in the diagnosis of Alzheimer’s disease (AD), manifesting mostly in the development of in vivo imaging methods that allow for the detection of pathological changes in AD by magnetic resonance imaging (MRI) and positron emission tomography (PET) scans. Many of these imaging methods, however, use agents that probe amyloid fibrils and plaques–species that do not correlate well with disease progression and are not present at the earliest stages of the disease. Amyloid β oligomers (AβOs), rather, are now widely accepted as the Aβ species most germane to AD onset and progression. Here we report evidence further supporting the role of AβOs as pathological instigators of AD and introduce promising anti-AβO diagnostic probes capable of distinguishing the 5xFAD mouse model from wild type mice by PET and MRI. In a developmental study, Aβ oligomers in 5xFAD mice were found to appear at 3 months of age, just prior to the onset of memory dysfunction, and spread as memory worsened. The increase of AβOs is prominent in the subiculum and correlates with concomitant development of reactive astrocytosis. The impact of these AβOs on memory is in harmony with findings that intraventricular injection of synthetic AβOs into wild type mice induced hippocampal dependent memory dysfunction within 24 h. Compelling support for the conclusion that endogenous AβOs cause memory loss was found in experiments showing that intranasal inoculation of AβO-selective antibodies into 5xFAD mice completely restored memory function, measured 30–40 days post-inoculation. These antibodies, which were modified to give MRI and PET imaging probes, were able to distinguish 5xFAD mice from wild type littermates. These results provide strong support for the role of AβOs in instigating memory loss and salient AD neuropathology, and they demonstrate that AβO selective antibodies have potential both for therapeutics and for diagnostics.
Highlights
General Alzheimer’s DiseaseMore than 6 million Americans are currently living with Alzheimer’s disease (AD), and Alzheimer’s-related deaths have increased 145% from 2000 to 2019 (Alzheimer’s Association, 2021)
Transgenic 5xFAD Novel Object Recognition/Novel Location Recognition Amyloid plaque development and intraneuronal Aβ42 accumulation are well-established in the 5xFAD transgenic (Tg) mouse model of Alzheimer’s disease
In order to characterize how memory loss correlates with amyloid β oligomer (AβO) in the 5xFAD mice, we used the wellestablished novel object recognition (NOR) task for non-spatial memory (Cohen and Stackman, 2015; Denninger et al, 2018) and the novel location recognition (NLR) task for spatial memory (Antunes and Biala, 2012; Grayson et al, 2015; Denninger et al, 2018)
Summary
More than 6 million Americans are currently living with Alzheimer’s disease (AD), and Alzheimer’s-related deaths have increased 145% from 2000 to 2019 (Alzheimer’s Association, 2021). The financial burden is even more staggering–Alzheimer’s and other dementias have cost the United States more than $600 billion in medical expenses and unpaid care in 2021 (Alzheimer’s Association, 2021). Despite the great personal and economic burden, progress toward developing effective diagnostics and therapeutics remains slow. Aduhelm R ( known as Aducanumab) was recently approved as a treatment for AD (Investor Relations, 2021), the first in more than a decade, but it still focuses on Aβ elimination rather than specific amyloid β oligomer (AβO) targets. As AD burden is expected to increase drastically with the aging population, improved diagnostics and therapeutics are more urgent than ever. Amyloid β Oligomers as a Biomarker for Early Alzheimer’s Disease
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