Fig. 2.
Alzheimer’s disease antibody approaches and associated mechanisms. a Amyloid precursor protein (APP) is cleaved sequentially by β-site APP cleaving enzyme (BACE1) and the γ-secretase complex to give rise to toxic beta amyloid (Aβ). Two antibody approaches to mitigate the toxic effects of Aβ include reducing the initial cleavage of APP by BACE1 with an antibody. A second, and more common, approach is to clear existing Aβ with antibodies targeting Aβ directly. b Two models for how anti-Aβ clears amyloid from the brain have been proposed. The “direct action” hypothesis postulates that systemically delivered anti-Aβ antibodies cross the blood–brain barrier and promote clearance of amyloid by activating microglia, inhibiting Aβ aggregation, promoting Aβ disaggregation, and/or directly inhibit Aβ oligomer toxicity to neurons. The “peripheral sink” hypothesis proposes that Aβ captured in the periphery (blood vessels) shifts the equilibrium of Aβ and pulls amyloid from the brain. c Recent evidence supports a prion-like spreading of tau from one neuron to neuron. We propose that immunologic approaches to tau may act primarily by reducing tau spreading, as anti-tau antibodies cross the blood–brain barrier and bind extracellular tau blocking its ability to seed pathology in adjacent neurons