**1. Introduction**

The removal of accumulated amyloid peptide in the brain is carried out by several mecha‐ nisms. The clearance of Aβ by nonenzymatic pathway is performed as follows: the total flux of the interstitial fluid (ISF) into the cerebrospinal fluid (CSF) accompanied by the ISF drainage pathway, phagocytosis by microglial or astrocytic cells, and a mechanism named peripheral sink(transportthroughthebloodvesselwallsintothecirculation);thelastonecouldberegulated by different receptors.

The enzymatic pathway uses the proteolytic machinery in the brain in order to clean the Aβ excess and includes the participation of multiple Aβ-degrading enzymes (ADE) implicated in the clearance of the different Aβ peptides, which include neprilysin, insulin-degrading enzyme, matrix metalloproteinase-9, glutamate carboxypeptidase II, the mitochondrial human preprotease, and others.

Finally, the last Aβ clearance mechanism involved in the Aβ degradation is related with the proteasome and Aβ degradation by autophagy. The proteasome is important for the degra‐ dation of worn out and misfolded proteins. Decreased proteasome activity has been implicated in Alzheimer's disease (AD) and proteasome inhibition induces autophagy. Autophagy is a catabolic process involved in the degradation of aberrant organelles and macromolecules, into double membrane vesicles, and delivers it to lysosomes for degradation and the eventual recycling of the resulting macromolecules, and more recently, autophagy has been related with Aβ clearance, but it is still unknown whether autophagy is beneficial or deleterious to AD neurons as the autophagosome has been suggested as a site of amyloid-β (Aβ) generation. In addition, there is little information about the autophagic processes on neurons or microglia involved in the degradation of amyloid peptides.

A series of studies on the Aβ clearance mechanism provide new insight into the pathogene‐ sis of AD at the molecular level and suggest a new target for the development of novel therapeutics. There are a lot of publications dealing with signaling pathways of Aβ synthe‐ sis and related enzymes but the identification of molecules responsible for Aβ clearance pathways and their mechanistic links to AD is still a matter of debate. The recent results have shown that Aβ-degrading enzymes have played an important role in reducing AD patholo‐ gy in both cell and animal models. However, the induction of intracellular clearance of Aβ42 by autophagy is becoming an important proposed mechanism to improve the degradation of Aβ peptides.
