How Alzheimer’s Aβ propagates and triggers tau pathology in intact neurons

Abstract

Alzheimer’s disease begins with Aβ accumulation, progresses to tau aggregates and results in widespread neurodegeneration^1-3. Simultaneous propagation of Aβ aggregates from very limited to wide and distant brain regions is one of the outstanding events in the early stage. Here, we demonstrate that the neurovascular unit^4,5 comprising capillaries and pericytes, the machinery supplying oxygen and glucose to neurons, is also the machinery for propagating effector molecules that impose Alzheimer’s pathologies on intact neurons. We discovered two distinct signaling cascades, one activated in capillary endothelial cells and the other in pericytes. At the origin of either cascade, we identified amylospheroid (ASPD)^6,7, a highly toxic 30-mer assembly of Aβ, and its sole target NKAα3⁸, a neuron-specific isoform of Na⁺,K⁺-ATPase^9,10 but present in endothelial cells and pericytes. In endothelial cells, ASPD binding to NKAα3 releases angiotensin II, which increases β-secretase in intact neurons, causing a huge increase of Aβ₄₂and resultant accumulation. In pericytes, ASPD binding to NKAα3 releases an unknown effector molecule that activates δ-secretase in intact neurons, further augmenting Aβ₄₂and producing pathogenic tau_1-368 fragment. Thus, Aβ and tau pathologies are directly linked. Stopping the signaling cascades near the origin by inhibiting ASPD-NKAα3 interaction⁸ may provide a new therapeutic approach.