Amyloid β (Aβ) is constantly metabolized, and the homeostasis of cerebral Aβ represents a dynamic balance between synthesis, reuptake, and clearance. Any factors that disturb this balance is likely to cause Aβ accumulation. It has been suggested that the clearance or degradation of Aβ, rather than its synthesis, is more critical in the accumulation of Aβ, especially in the late-onset, common cases of Alzheimer disease (AD). Thus, modulation of Aβ clearance may be an important early strategy for reducing Aβ accumulation and disease progression.
Mechanisms of Aβ Clearance and the Defective-Clearance Hypothesis
An imbalance between production and clearance of Aβ is a key driver momentum of the sophisticated pathological cascade of AD. It is caused by overproduction of Aβ or, more commonly, by defective clearance from the brain. The cerebral Aβ clearance is a complex process mediated by various systems and cell types, including vascular transport across the blood-brain barrier (BBB), glymphatic drainage, and engulfment and degradation by resident microglia and infiltrating innate immune cells. Though each system may contribute to Aβ clearance to varying extents, their summed effects are critical for Aβ homeostasis. This implies that perturbations of any process may predispose to the accumulation of pathological Aβ and thus lead to the development of AD.
| Mechanisms of Cerebral Aβ Clearance | Description | Examples of Identified Molecules |
| Enzymatic pathway | Many peptidases and proteinases, known collectively as Aβ-degrading enzymes (ADE), affect Aβ levels. They cleave either at a single site or multiple sites within Aβ. | neprilysin, insulin-degrading enzyme, matrix metalloproteinase-9, glutamate carboxypeptidase II, angiotensin-converting enzyme |
| Intracellular degradation systems | Autophagy, endosomal/lysosomal degradation, and the ubiquitin-proteasome system degradation occur in cells that either absorb or engulf Aβ forms. | mTOR signal pathway |
| Clearance mediated by extracellular chaperones | Transport of Aβ across the BBB is one method by which these peptides are eliminated from the brain parenchyma. This event requires a specialized transport system of molecular chaperones. | members of the LDL receptor (LDLR) family |
| Glymphatic clearance | The glymphatic system is a pathway of brain-wide waste clearance for small proteins and metabolites. | / |
| Myeloid cell-mediated phagocytosis | Activation of brain-resident microglia and infiltrating blood-borne monocyte-derived macrophages is essential for the physiological Aβ clearance. | LRP-1, scavenger receptors, toll-like receptors, RAGE, and TREM-2 |
Strategies in Increasing Aβ Clearance
According to mechanisms of Aβ clearance, the examples of strategies for increasing Aβ clearance are listed below:
Immunotherapy to Increase Aβ Clearance
The immunotherapy approach involves either challenging the organism with Aβ or Aβ fragments to elicit an immune response that produces antibodies selective for Aβ (i.e., active immunization) or dispensing specific anti-Aβ monoclonal antibodies prepared exogenously (i.e., passive immunization). Immunotherapy is in principle the most straightforward and extensively developed approach but has been more challenging than expected and has faced major problems in terms of safety and efficacy.
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