Cathepsin D as a therapeutic target in Alzheimer’s disease

Several neurodegenerative diseases are characterized by the accumulation of ubiquitin-positive protein aggregates in affected brain regions [1]. These misfolded/aberrant proteins are toxic for neuronal function and contribute to neurodegeneration. Protein quality control, including autophagy and proteasome system, is necessary for the removal of aggregated proteins that are harmful for the brain. Autophagy-lysosomal system plays crucial roles in both normal cellular homeostasis and disease states. Indeed, the constitutively active autophagy is critical for post-mitotic cells, such as neurons that cannot simply dilute harmful molecules through cell division [2]. The lysosomal system consists of communicating acidic compartments which contain over 80 lysosomal hydrolases, including proteases, nucleases, phosphatases, sulfatases, lipases, and glycosidase. Lysosomal cathepsins can be divided into three groups: cysteine (cathepsins B, C, F, H, K, L, O, S, V, W, and X), aspartic (cathepsins D and E), and serine (cathepsin G) proteases [3]. The aspartic cathepsin D and some of the cysteine cathepsins are ubiquitous and among the most abundant lysosomal proteases. The acidic environment of the lysosomal lumen, resulting from the action of the vacuolar H+ -ATPase, facilitates the degradation process by loosening the structures of macromolecules and is optimal for the activity of lysosomal hydrolases [3]. In the Alzheimer’s disease (AD) brain, progressive abnormalities of the endosomal-lysosomal system, such as increase in size and volume of early endosomes, are a prominent neuropathological feature [2]. Amyloid beta (Aβ) peptide has also been detected in these enlarged endosomes that are immunopositive for the early endosomal marker rab5 [4]. Indeed, several studies have identified the endosomal-lysosomal pathway as an important regulator of the processing of amyloid precursor protein (APP) [5]. Early endosomes produce Aβ from APP in normal cells and mediate the uptake of Aβ and soluble APP. The upregulation of the lysosomal system occurs in vulnerable cell populations and results in increased numbers of lysosomes with elevated expression of lysosomal hydrolases [6]. As AD pathogenesis progresses, lysosomal dysfunction appears to occur with the build-up of vacuolar structures and the accumulation of Aβ. The degeneration of the compromised neurons leads to the release of these structures into the extracellular space, where they associate with deposits of Aβ