Vascular mechanisms of AD pathogenesis: the putative role of a defective blood-brain barrier, serum Aβ42, and neuron-binding autoantibodies

Mounting evidence suggests that cerebrovascular damage may play a significant role in disease progression of AD, including findings demonstrating consistent morphological evidence of BBB dysfunction in AD brains. Furthermore, recent research has provided support for the critical contribution of intraneuronal accumulation of Aβ peptide to AD pathology. However, while several studies have indicated preliminary evidence that Aβ peptides in the AD brain may originate in the blood via chronic BBB leak, this source has not yet been directly and systematically tested. To address this possibility, we developed an experimental mouse model combining chronic application of pertussis toxin and introduction of soluble Aβ42 into the venous blood to empirically test whether long-standing disruption of BBB integrity can trigger the appearance of pathological features simulating AD. Mice dually exposed to pertussis toxin and soluble Aβ42 on a chronic basis were found to demonstrate clear evidence of perturbation of the BBB and manifested an associated cascade of pathological features, including extravasation of plasma Aβ42 and IgG and entry into the brain parenchyma, neuronal binding of IgG, neuronal as well as synaptic Aβ42 binding, and intracellular accumulation of Aβ42. Importantly, regional deposition and intracellular internalization of Aβ42 conformed to a selective pattern of distribution analogous to human AD and was generally co-localized with regions of neuronal IgG binding, suggesting that the two may be mechanistically linked, as well as markers of astrocytic activation and subtle signs of dendritic and synaptic degradation suggesting early inflammatory and adverse neuro- functional repercussions of neuronal deposition of Aβ42 and IgG. With respect to cognitive functioning, animals subjected to this manipulation displayed a pattern of variable disruption of the acquisition of learned behaviors, a more consistent and preferential deficit in the capacity for long-term retention, and an increased susceptibility to interference in selective attention. Regarding unlearned behaviors, treated animals exhibited a mild up-regulation of emotionality and altered stress reactivity. Taken together, neuropathological sequelae of BBB disturbance converge with those manifested in the behavioral and cognitive domains, in corresponding to a common, emergent, phase of AD- like pathology. Collectively, these results indicate that chronic disruption of the BBB and the resulting influx of exogenous Aβ42 and anti-neuronal autoantibodies from the blood can mimic the pathological events of AD, and thus provides compelling evidence implicating the blood as a likely source of amyloid that deposits in AD brains via chronic BBB dysfunction and anti-neuronal autoantibody-induced endocytosis as a likely means of entry into neurons.Ph.D.Includes bibliographical referencesIncludes vitaby Henya A. Grossma