Clearance of amyloid β-protein and its role in the spreading of Alzheimer's disease pathology

Amyloid beta-protein (A beta) containing amyloid plaques and abnormal phosphorylated tau-protein containing neurofibrillary tangles (NFTs) are hallmark lesions of Alzheimer's disease. Both A beta plaques and NFTs show hierarchical patterns in which the areas of the brain are subsequently affected by A beta plaques and NFTs, respectively (Braak and Braak, 1991; Thal et al., 2002). A beta plaques start to develop in the neocortex (phase 1) and spread from there into allocortical regions (phase 2), diencephalon, basal forebrain and striatum (phase 3), midbrain and medulla oblongata (phase 4), and finally into the pons and the cerebellum (phase 5) (Thal et al., 2002). The first NFTs in the brain hemispheres are found in the transentorhinal cortex (stage I), then in the entorhinal cortex (stage II), the hippocampus (stage III), the temporal cortex (stage IV), further neocortical areas except the primary fields (stage V), and, finally, also in primary cortical areas, such as the primary visual cortex (stage VI) (Braak and Braak, 1991). Axonal connections between subsequently affected brain regions suggest that AD pathology spreads along neuronal pathways (Thal et al., 2002; Brarak and Del Tredici, 2011). Insufficient clearance of A beta has been considered to play an essential role in the pathogenesis of AD. Clearance mechanisms that contribute to A beta elimination from brain are cellular enzymatic proteolysis in glial cells, neurons or in the extracellular space (Qin et al., 1998; Yamaguchi et al., 1998; Iwata et al., 2000; Thal et al., 2000; Farris et al., 2003), transport through the blood-brain barrier (Shibata al., 2000; Ito et air, 2007), and perivascular drainage (Weller et air, 2008) (Figure 1A). Here, I will discuss the potential impact of impaired A beta clearance on propagation mechanisms for A beta and tau.