Cerebrospinal Fluid BACE1 Activity and Brain Amyloid Load in Alzheimer's Disease

Received Oct 17, 2011; Accepted Nov 2, 2011

1. Introduction

The cerebrospinal fluid (CSF) is in close contact with the extracellular space of the central nervous system; therefore, pathological changes such as those due to neurodegeneration are reflected in CSF and alterations of biomarkers can yield important mechanistic and diagnostic information on disease processes. In Alzheimer’s disease (AD), a growing number of CSF biomarkers are studied, some of which mirror important events in the pathogenic cascade. These markers include several indicators of changes related to the amyloid cascade such as amyloid $\beta$ 42 (A$\beta$42), total tau and phosphorylated tau [1]. The amyloid hypothesis of AD argues a cerebral accumulation of amyloid as primary driver of AD pathogenesis, including amyloid plaque deposition, neurofibrillary tangle formation, synapse loss, and neuronal cell death [2]. The amyloid deposits of insoluble protein material mainly contain high levels of the 40 and 42 amino acid long A$\beta$, which is produced through the cleavage of a membrane-bound amyloid precursor protein (APP) by the $\beta$- and $\gamma$-secretases. The cleavage of APP by the main cerebral $\beta$-secretase ($\beta$-site APP-cleaving enzyme 1, BACE1) [3] occurs at the N-terminus of the A$\beta$-domain and results in secreted soluble APP β (sAPP$\beta$) and a C-terminal fragment (C99) [4], which subsequently undergoes cleavage by γ-secretase producing Aβ. The crucial role of BACE1 in AD pathogenesis is highlighted by its increased enzyme activity and protein concentration in AD brains [5]. Several previous studies have shown that BACE1 activity can readily be detected in CSF with activity increases in mild cognitive impairment (MCI) and clinically diagnosable AD [6–8]. The relevance of BACE1 in the amyloid cascade is also underscored by its positive association with the CSF products of APP cleavage, including Aβ40 and sAPPβ [9]. Therefore, the value of BACE1 as a clinical biomarker for AD pathology and for anti-amyloid treatment effects is currently under debate. Further in-vivo studies are urgently needed in order to explore the association between CSF BACE1 activity and amyloid pathology in AD; modern imaging techniques might play an important role in this regard since they are able to provide information about clinically suspected cerebral pathology and...

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