The Therapeutic and Diagnostic Potential of Amyloid β Oligomers Selective Antibodies to Treat Alzheimer’s Disease

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.

Elucidation of Amyloid-Beta’s Gambit in Oligomerization: Truncated Aβ fragments of residues Aβ1-23, Aβ1-24 and Aβ1-25 rapidly seed to form SDS-stable, LMW Aβ oligomers that impair synaptic plasticity

“…LysN cleavage products were subjected to PRM analysis and the calculated total peptide areas, as a sum of all MS 2 b-ion (b2 to b8) transitions (bottom, left), were used to estimate the relative abundance (histogram, right) of the different Aβ isoforms found within HMW oligomers. (Lanes 1-8 are identical Aβ samples but loaded at high (1, 3, 5) and low (2, 4, 6) concentrations, lane 8 = MWM). d WB analysis of Aβ40 (left) and Aβ42 (right) ADDLs.…”

“…Significant IHC staining of Aβ oligomers was reported using different conformation specific antibodies (3) with binding properties against large (≥80kDa) Aβ assemblies (59). The lack in JD1 staining of amyloid plaques may not appear surprising, given JD1’s binding specificity for LMW Aβ assemblies and the overall scarcity of Aβ oligomers reported in the human brain, which is an observation also made by others using different anti-oligomer antibodies (3,28,61). Nevertheless, our high-resolution array tomography clearly shows co-localization of JD1 positive species at post-synaptic terminals, which is in line with earlier reports, using different conformational specific antibodies (34).…”

“…Our understanding of JD1 binding properties give rise to important Aβ target “loopholes” associated with earlier developed anti-conformational antibodies. Yet, it remains to be determined, if other antibody molecules, such as the anti-oligomer ACU 193 (3) or anti- protofibril antibody lecanemab, currently undergoing clinical validation (56, 57), provide similar binding properties for the here described LMW Aβ assemblies. Our observation on aducanumab’s decreased binding affinity for LMW oligomeric assemblies has not been reported before, and this finding is somehow surprising, because aducanumab’s binding epitope is known to span the N-terminal region of residues 3-6.…”

“…Significant IHC staining of Aβ oligomers was reported using different conformation specific antibodies (3) with binding properties against large (≥80kDa) Aβ assemblies (59). The lack in JD1 staining of amyloid plaques may not appear surprising, given JD1’s binding specificity for LMW Aβ assemblies and the overall scarcity of Aβ oligomers reported in the human brain, which is an observation also made by others using different anti-oligomer antibodies (3,28,61).…”

“…As a consequence significant effort has been made in the past to gain insight into early, “molecular triggers” associated with pathological amyloid-beta (Aβ) aggregation, because Aβ oligomers are known to play a causative role in early synaptic dysfunction and cognitive decline in patients suffering from dementia (2). Therefore, Aβ oligomers are widely accepted as an appealing diagnostic and therapeutic target (3) in Alzheimer’s disease (AD). However, structural characterization of Aβ oligomers remains a challenging endeavour (4), which is mainly due to the labile and polymorphic nature found with these oligomeric entities.…”