Fight Aging!

Alzheimer's disease is a complex degenerative failure of a complex system, the brain. This complexity is illustrated by the continuing debate over which of the many identified mechanisms are the primary cause. Is it amyloid-β aggregation, or some aspect of the halo of biochemistry associated with that aggregation, or is it chronic inflammation, or cellular senescence in supporting cells of the brain, or vascular dysfunction and leakage of the blood-brain barrier, or neurofibrillary tangles, or the presence of persistent viruses. All of these mechanisms interact with one another, and the direction of causation between any specific pair of mechanisms is also up for debate. Researchers are in many cases challenged by the inability to affect one mechanism in isolation of the others; even immunotherapies to clear amyloid-β have side-effects on tissues and the immune system.

In today's open access paper, researchers point out that most Alzheimer's patients exhibit cerebral amyloid angiopathy, deposition of amyloid-β into blood vessel walls leading to dysfunction, leakage, and rupture of microvessels. This results in damage to surrounding brain tissue and passage of inappropriate cells and molecules into the brain, provoking inflammation, among other consequences. The paper delves into mechanisms by which amyloid-β aggregation might cause dysfunction of the blood-brain barrier wrapping blood vessels in the brain and thus also the problems that arise from leakage of the blood-brain barrier. This is one example of an argument for a specific direction of causation between processes known to be involved in Alzheimer's disease. There are many such arguments, and not all of them agree with the one set out in this paper!

Endothelial leakiness elicited by amyloid protein aggregation

The most influential paradigm concerning Alzheimer's disease (AD) pathology is the amyloid cascade hypothesis and its modifications thereafter, where amyloid beta (Aβ) evolves from disordered monomers to toxic oligomers and amyloid fibrils through molecular self-assembly, modulated by environmental factors such as pH, temperature, metals, chaperones, and cell membranes. Accordingly, much effort over the past three decades has been made towards inhibiting or clearing the toxic Aβ aggregates, employing small molecules, peptidomimetics, antibodies, and, more recently, nanoparticles. A lack of clinical success, however, has shrouded these efforts, suggesting the pathophysiology of AD is multifactorial as its triggers.

Indeed, it has now been realized that, in addition to Aβ amyloidogenesis, tauopathies, apolipoprotein E, and neuroimmune activation are all causative to neurodegeneration in AD. The great (80-90%) correlation between AD subjects and patients carrying cerebral amyloid angiopathy (CAA) further suggests an important role of endothelial integrity in the development of AD pathogenesis, also evidenced by observations of cerebral endothelial dysfunction and microvascular injury induced by Aβ. Intriguingly, while Aβ originates from the proteolytic cleavage of amyloid precursor protein (APP) in endosomal membrane, deposits of Aβ are seen throughout the central nervous system, cerebral blood vessels, cerebrospinal fluid, and the plasma. Aβ-mediated vasoactivity, vascular capillary constriction, blood flow reduction, and paracellular transport have been reported with endothelial monolayers, blood-brain barrier (BBB), and biopsied human and rodent brain tissues, in connection with the production of reactive oxygen species (ROS), modified cytoskeletal network, altered tight-junction protein expression, and signaling to pericytes.

Here we show amyloid protein-induced endothelial leakiness (APEL) in human microvascular endothelial monolayers as well as in mouse cerebral vasculature. Using signaling pathway assays and discrete molecular dynamics, we revealed that the angiopathy first arose from a disruption to vascular endothelial (VE)-cadherin junctions exposed to the nanoparticulates of Aβ oligomers and seeds, preceding the earlier implicated proinflammatory and pro-oxidative stressors to endothelial leakiness. These findings were analogous to nanomaterials-induced endothelial leakiness (NanoEL), a major phenomenon in nanomedicine depicting the paracellular transport of anionic inorganic nanoparticles in the vasculature. As APEL also occurred in vitro with the oligomers and seeds of alpha synuclein, this study proposes a paradigm for elucidating the vascular permeation, systemic spread, and cross-seeding of amyloid proteins that underlie the pathogenesis of AD and Parkinson's disease.