{"id":101,"date":"2019-10-14T03:03:33","date_gmt":"2019-10-14T07:03:33","guid":{"rendered":"http:\/\/www.creativebiomart.org\/alzheimacy\/?page_id=101"},"modified":"2020-09-06T23:52:44","modified_gmt":"2020-09-07T03:52:44","slug":"increasing-amyloid-%ce%b2-clearance","status":"publish","type":"page","link":"https:\/\/www.creativebiomart.net\/alzheimacy\/target\/abeta-amyloid-pathway-as-drug-targets\/increasing-amyloid-beta-clearance\/","title":{"rendered":"Increasing Amyloid \u03b2 Clearance"},"content":{"rendered":"

Amyloid \u03b2 (A\u03b2)\u00a0is constantly metabolized, and the homeostasis of cerebral A\u03b2 represents a dynamic balance between synthesis, reuptake, and clearance. Any factors that disturb this balance is likely to cause A\u03b2 accumulation. It has been suggested that the clearance or degradation of A\u03b2, rather than its synthesis<\/a>, is more critical in the accumulation of A\u03b2, especially\u00a0in the late-onset, common cases of Alzheimer disease (AD). Thus, modulation of A\u03b2 clearance may be an important early strategy for reducing A\u03b2 accumulation and disease progression.<\/p>\n

Mechanisms of A\u03b2 Clearance and the Defective-Clearance Hypothesis <\/strong><\/p>\n

An\u00a0imbalance between production and clearance of A\u03b2\u00a0is a key driver\u00a0momentum of the sophisticated pathological cascade of\u00a0AD. It is caused by overproduction of A\u03b2\u00a0or, more commonly, by defective clearance from the brain.\u00a0The\u00a0cerebral A\u03b2 clearance is a complex process mediated by various systems and cell types, including vascular transport across the blood-brain barrier (BBB),\u00a0glymphatic drainage,\u00a0and engulfment and degradation by resident microglia and infiltrating innate immune cells. Though\u00a0each system may contribute to\u00a0A\u03b2\u00a0clearance to varying extents, their summed effects are\u00a0critical for A\u03b2\u00a0homeostasis. This implies\u00a0that perturbations of any process\u00a0may predispose to\u00a0the accumulation of pathological A\u03b2\u00a0and thus lead to the development of AD.<\/p>\n\n\n\n\n\n\n\n\n
Mechanisms of Cerebral A\u03b2 Clearance <\/strong><\/td>\nDescription <\/strong><\/td>\nExamples of Identified Molecules <\/strong><\/td>\n<\/tr>\n
Enzymatic pathway<\/td>\nMany peptidases and proteinases, known collectively as A\u03b2-degrading enzymes (ADE), affect A\u03b2 levels. They cleave either at a single site or multiple sites within A\u03b2.<\/td>\nneprilysin, insulin-degrading enzyme, matrix metalloproteinase-9, glutamate carboxypeptidase II, angiotensin-converting enzyme<\/td>\n<\/tr>\n
Intracellular degradation systems<\/td>\nAutophagy, endosomal\/lysosomal degradation, and the ubiquitin-proteasome system degradation occur in cells that either absorb or engulf A\u03b2 forms.<\/td>\nmTOR signal pathway<\/td>\n<\/tr>\n
Clearance mediated by extracellular chaperones<\/td>\nTransport of A\u03b2 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.<\/td>\nmembers of the LDL receptor (LDLR) family<\/td>\n<\/tr>\n
Glymphatic clearance<\/td>\nThe glymphatic system is a pathway of brain-wide waste clearance for small proteins and metabolites.<\/td>\n\/<\/td>\n<\/tr>\n
Myeloid cell-mediated phagocytosis<\/td>\nActivation of brain-resident microglia and infiltrating blood-borne monocyte-derived macrophages is essential for the physiological A\u03b2 clearance.<\/td>\nLRP-1, scavenger receptors, toll-like receptors, RAGE, and TREM-2<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Strategies in<\/strong>\u00a0Increasing<\/strong>\u00a0A\u03b2 Clearance <\/strong><\/p>\n

According to mechanisms of A\u03b2 clearance, the examples of strategies for increasing A\u03b2 clearance are listed below:<\/p>\n