Abstract
Amyloid β-protein (Aβ) containing amyloid plaques and abnormal phosphorylated τ-protein containing neurofibrillary tangles (NFTs) are hallmark lesions of Alzheimer's disease. Both Aβ plaques and NFTs show hierarchical patterns in which the areas of the brain are subsequently affected by Aβ plaques and NFTs, respectively (Braak and Braak, 1991; Thal et al., 2002). Aβ 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; Braak and Del Tredici, 2011). Insufficient clearance of Aβ has been considered to play an essential role in the pathogenesis of AD. Clearance mechanisms that contribute to Aβ elimination from brain are cellular enzymatic proteolysis in glial cells, neurons or in the extracellular space (Qiu 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 et al., 2000; Ito et al., 2007), and perivascular drainage (Weller et al., 2008) (Figure (Figure1A1A). Figure 1 Schematic representation of Aβ clearance and propagation. (A) Aβ clearance mechanisms: enzymatic clearance within neurons (N) and glial cells [here shown in the example is an astrocyte (AG)] or in the extracellular space (ECS) (Qiu et ... Here, I will discuss the potential impact of impaired Aβ clearance on propagation mechanisms for Aβ and τ.
Highlights
Biophysical and Biochemical Prerequisites for Amyloid β-protein (Aβ) and τ Protein AggregationProtein aggregation takes place once a critical concentration of proteins has been passed
Amyloid β-protein (Aβ) containing amyloid plaques and abnormal phosphorylated τ-protein containing neurofibrillary tangles (NFTs) are hallmark lesions of Alzheimer’s disease
Spreading of Aβ pathology means that Aβ aggregation and deposition already took place at least in the neocortex and a second region becomes involved in this process
Summary
Protein aggregation takes place once a critical concentration of proteins has been passed. Fibril formation sets in after a concentration-dependent lag-phase, i.e., the time interval between passing a critical concentration and forming fibrils (Figure 1B) (Chirita et al, 2005). Proteins in general differ in their capability to aggregate, and their assembly can be further modulated by chaperones (Gething and Sambrook, 1992). Posttranslational modifications of proteins, such as N-terminal truncation and pyroglutamate formation, phosphorylation, or glycation increase the tendency of Aβ or τ to form aggregates (Necula and Kuret, 2004; Schlenzig et al, 2009; Kumar et al, 2011). Seeds of preaggregated fibrils can reduce the lag-phase dramatically and trigger immediate aggregation (Figure 1B)
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