BACE1 levels are increased in plasma of Alzheimer’s disease patients compared with matched cognitively healthy controls

Written by Manzine PR, da Silva Souza M, Cominetti MR

In Alzheimer’s disease (AD), the amyloidogenic pathway results in the production of Aβ peptide from AβPP. Aβ has a hydrophobic nature and aggregates extracellularly, forming senile plaques [1]. In turn, neurofibrillary tangles are intracellular fibrillar aggregates of the hyperphosphorylated microtubule-associated Tau protein. Together, these entities are the key microscopic neuropathological hallmarks of AD [2].
In AD, the amyloidogenic pathway is the predominant route of AβPP cleavage, when it is first cleaved at the amino terminus by BACE1. This cleavage produces a large soluble secreted segment (sAβPPβ) and a membrane bound CTFβ of AβPP (also known as C99). Cleavage of CTFβ by γ-secretase results in the production of the Aβ40 and Aβ42 species [3]. In the nonamyloidogenic route, AβPP is cleaved by α-secretases (mainly ADAM10) in the middle of Aβ, which generates sAβPPα and C83 fragments, preventing Aβ liberation and consequent aggregation [4].

BACE1 is a 70 kDa type I transmembrane aspartyl protease formed by 501 amino acids with an extracellular domain containing two active aspartyl residues at amino acid positions 93 and 289 [5]. Several reports indicate an increase in BACE protein levels and activity in cerebrospinal fluid (CSF) and brain tissue of AD patients, as compared with control subjects, both in human or experimental models [6–14]. In several cases, this increase appears to be correlated with amyloid load [6,7,10,13,14].

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