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Review
. 2023 Aug 31;32(4):216-246.
doi: 10.5607/en23014.

Advances in Amyloid-β Clearance in the Brain and Periphery: Implications for Neurodegenerative Diseases

Rahat Ullah  1   2 , Eun Jeong Lee  3
Affiliations
Review

Advances in Amyloid-β Clearance in the Brain and Periphery: Implications for Neurodegenerative Diseases

Rahat Ullah et al. Exp Neurobiol. .

Abstract

This review examines the role of impaired amyloid-β clearance in the accumulation of amyloid-β in the brain and the periphery, which is closely associated with Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). The molecular mechanism underlying amyloid-β accumulation is largely unknown, but recent evidence suggests that impaired amyloid-β clearance plays a critical role in its accumulation. The review provides an overview of recent research and proposes strategies for efficient amyloid-β clearance in both the brain and periphery. The clearance of amyloid-β can occur through enzymatic or non-enzymatic pathways in the brain, including neuronal and glial cells, blood-brain barrier, interstitial fluid bulk flow, perivascular drainage, and cerebrospinal fluid absorption-mediated pathways. In the periphery, various mechanisms, including peripheral organs, immunomodulation/immune cells, enzymes, amyloid-β-binding proteins, and amyloid-β-binding cells, are involved in amyloid-β clearance. Although recent findings have shed light on amyloid-β clearance in both regions, opportunities remain in areas where limited data is available. Therefore, future strategies that enhance amyloid-β clearance in the brain and/or periphery, either through central or peripheral clearance approaches or in combination, are highly encouraged. These strategies will provide new insight into the disease pathogenesis at the molecular level and explore new targets for inhibiting amyloid-β deposition, which is central to the pathogenesis of sporadic AD (amyloid-β in parenchyma) and CAA (amyloid-β in blood vessels).

Keywords: Alzheimer’s disease (AD); Amyloid-β clearance; Brain and periphery; Cerebral amyloid angiopathy (CAA).

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Figures

Fig. 1
Fig. 1
Reduced clearance of amyloid-β in brain resulting in sporadic AD (amyloid-β deposition in parenchyma) and CAA (amyloid-β deposition in blood vessels).
Fig. 2
Fig. 2
Clearance mechanisms for amyloid-β in the brain and periphery. Central Clearance of amyloid-β in the brain. In the brain, amyloid-β clearance occurs through (1) enzymatic and (2) non-enzymatic pathways. Enzymatic clearance involves multiple amyloid-β-degrading enzymes (AβDPs) such as (i) zinc metalloendopeptidase, (ii) thiol-dependent metalloendopeptdiase, (iii) serine protease, (iv) cystein protease, and (v) matrix metalloproteinase. Non-enzymatic clearance mechanisms include clearance through (1) BBB, (2) cellular-mediated clearance involving (i) neurons, (ii) microglia, (iii) astrocytes, (iv) endothelial cells and (v) pericytes. (3) intestinal fluid (ISF) bulk-flow-mediated clearance through the perivascular drainage or the glymphatic pathway and (4) cerebrospinal fluid (CSF)-mediated clearance, which involves absorption into the circulatory system or the lymphatic system. Peripheral clearance of amyloid-β in blood or peripheral organs. In blood, amyloid-β is degraded or cleared by proteases, AβDPs, blood cells such as monocytes or neutrophils, or transported by carriers such as erythrocytes, albumin, and lipoproteins to peripheral organs, where itis degraded by macrophages in the spleen or hepatocytes or excreted via the liver or kidney. Abbreviations: BBB, blood-brain barrier; RAGE, advanced glycosylation end product specific receptor; CSF, cerebrospinal fluid; LRP1, Low density lipoprotein receptor-related protein 1, ISF, interstitial fluid; ABC transporters, ATP-binding cassette transporter; BCSFB, blood-CSF barrier.
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