Clearance systems in the brain—implications for Alzheimer disease

Abstract

Accumulation of neurotoxic forms of amyloid-β (Aβ) and tau proteins is the pathological hallmark of Alzheimer disease (AD) Excess deposition of Aβ results from an imbalance between its production and clearance; in both early-onset and late-onset forms of AD, Aβ clearance seems already impaired at the prodromal stage Aβ is removed from the brain by various overlapping and interacting clearance systems: degradation, blood–brain barrier (BBB) transport, interstitial fluid (ISF) bulk flow, and cerebrospinal fluid (CSF) absorption into the circulatory and peripheral lymphatic systems Although most extracellular Aβ undergoes BBB clearance, the recently discovered glymphatic pathway seems to be important for Aβ clearance Specific BBB transporters for tau have not been identified, suggesting that clearance of tau is less complex than that of Aβ, and mainly relies on degradation, ISF bulk flow, and CSF absorption Precise understanding of the mechanisms of clearance dysfunction in AD is paramount to develop strategies to reduce excess deposition of neuroxic protein and to halt the related pathological changes