Role of Cdk5 in Amyloid-beta Pathology of Alzheimer’s Disease

Alzheimer’s Disease (AD) is a progressive neurodegenerative disease with irreversible cognitive impairment. So far, successful treatment and prevention for this disease are deficient in spite of delaying the progression of cognitive impairment and dementia. Cyclin dependent kinase 5 (Cdk5), a unique member of the cyclin-dependent kinase family, is involved in AD pathogenesis and may be a pathophysiological mediator that links the major pathological features of AD. Cdk5 dysregulation interferes with the proteolytic processing of Amyloid-beta Protein Precursor (APP) and modulates amyloidbeta (Aβ) by affecting three enzymes called α-, β- and γ-secretase, which are critical for the hydrolysis of APP. Given that the accumulation and deposition of Aβ derived from APP are a common hinge point in the numerous pathogenic hypotheses of AD, figuring out that influence of specific mechanisms of Cdk5 on Aβ pathology will deepen our understanding of AD.

Insight into inhibition of the human amyloid beta protein precursor (APP: PDB ID 3UMI) using (E)-N-(pyridin-2-ylmethylene)arylamine (LR) models: structure elucidation of a family of ZnX2-LRcomplexes

LRshows interactions with the human amyloid beta protein precursor (APP)viazinc atoms. Such interactions were confirmed from the X-ray diffraction studies.

Proteolytic processing of the amyloid-beta protein precursor of Alzheimer's disease

The proteolytic processing of the amyloid-beta protein precursor plays a key role in the development of Alzheimer's disease. Cleavage of the amyloid-beta protein precursor may occur via two pathways, both of which involve the action of proteases called secretases. One pathway, involving beta- and gamma-secretase, liberates amyloid-beta protein, a protein associated with the neurodegeneration seen in Alzheimer's disease. The alternative pathway, involving alpha-secretase, precludes amyloid-beta protein formation. In this review, we describe the progress that has been made in identifying the secretases and their potential as therapeutic targets in the treatment or prevention of Alzheimer's disease.

Trafficking of cell-surface amyloid beta-protein precursor. II. Endocytosis, recycling and lysosomal targeting detected by immunolocalization

Amyloid beta-protein (A beta) is a proteolytic fragment of the amyloid beta-protein precursor (beta PP). Progressive cerebral deposition of A beta is an early and invariant feature of Alzheimer's disease. The cellular trafficking of beta PP is of particular interest because understanding the production of A beta requires a comprehensive elucidation of the metabolic pathways of this protein. In addition, beta PP is a type I integral membrane glycoprotein that belongs to a class of molecules with both full length and secreted products. Recent evidence suggests that beta PP can be processed in an endosomal/lysosomal pathway. In the latter organelles, a number of beta PP carboxy-terminal derivatives are found, but the precise pathway and kinetics of beta PP trafficking from the cell surface remain unclear. To address these questions, we visualized directly the beta PP internalization pathway by following the localization and distribution of beta PP monoclonal antibodies added to intact beta PP-transfected Chinese hamster ovary cells. Using immunofluorescence and immunoelectron microscopy, beta PP was shown to be rapidly internalized via coated pits and vesicles, after which the molecules were transported to endosomes, prelysosomes, and lysosomes. Using a modified immunodetection protocol, we demonstrated the rapid recycling of endocytosed beta PP to the cell surface and its ultimate targeting to lysosomes. Because we recently found that endocytosis of cell surface beta PP is one route for the constitutive production of A beta, the recycling pathway for cell surface beta PP demonstrated here is a probable route for production of the critical A beta fragment.