Selective affinity of extravasated brain-reactive IgG autoantibodies for pyramidal neurons is linked to brain amyloid beta deposition, neuronal dysfunction, and cognitive decline.

Abstract

Amyloid beta plaques (APs) containing amyloid beta peptides (Aβ), blood-brain barrier (BBB) breakdown, and progressive cognitive decline are hallmarks of Alzheimer's disease (AD) pathology. Pathophysiological changes that initiate and perpetuate these hallmarks remain unresolved. We hypothesize that chronic extravasation of immunoglobulin Gs (IgGs) and Aβ via chronically impaired BBB promotes their interaction with pyramidal neurons (PNs). This interaction impairs PN function, consequentially initiates and perpetuates these AD-associated hallmarks. We tested our hypothesis associating neurocognitive decline with BBB breakdown in humans and a mouse model. In humans, antemortem neurocognitive status and postmortem BBB breakdown in their Brodmann area 39/40 were analyzed [AD, mild cognitive impairment (MCI), and no cognitive impairment (NCI) subjects, n=15]. Additionally, we tested the association between chronic BBB compromise, Aβ injection, and long-term memory in CD1 mice (10 months, male, n=33) with Pertussis toxin (PT) injection-induced BBB breach. This mouse-model comprised three injection groups: Saline only, PT+Saline, and PT+Aβ42. We used the immunohistochemistry technique and image-analysis software to track and quantify the fate of blood-borne Aβ42 in mouse brain by injecting synthetic, fluorescent-tagged monomeric Aβ42 (F-Aβ42). We used Lashley's III Maze and Water Maze to evaluate the impact of BBB breach and Aβ42 injection on animals' long-term memory. Brodmann areas 39/40 of AD subjects showed a greater incidence and extent of BBB breach than MCI and NCI subjects. Cognitive test results demonstrating reduced cognitive function for Brodmann areas 39/40 correlated with the extent of BBB breach. Likewise, PT+Aβ42 mice exhibited increased BBB permeability and selectively heightened immunoreactivity between PNs and extravasated IgGs compared to other groups. Since these IgGs target "self" epitopes in the brain parenchyma, we refer to this subset of IgGs as brain-reactive autoantibodies (BrAbs). Additionally, in PT+Aβ42 mice, we observed intraneuronal accumulations of F-Aβ42 in cortical and hippocampal PNs and significant impairment in long-term memory. In AD pathogenesis, BBB compromise induces chronic extravasation of BrAbs and Aβ, an event that serves as a mechanistic link that initiates and perpetuates Aβ deposition in PNs. Deposition of Aβ may perturb PN function and lead to progressive cognitive decline.