Employing new cellular therapeutic targets for Alzheimer's disease: a change for the better?

Abstract

Alzheimer's disease is a progressive disorder that results in the loss of cognitive function and memory. Although traditionally defined by the presence of extracellular plaques of amyloid-beta peptide aggregates and intracellular neurofibrillary tangles in the brain, more recent work has begun to focus on elucidating the complexities of Alzheimer's disease that involve the generation of reactive oxygen species and oxidative stress. Apoptotic processes that are incurred as a function of oxidative stress affect neuronal, vascular, and monocyte derived cell populations. In particular, it is the early apoptotic induction of cellular membrane asymmetry loss that drives inflammatory microglial activation and subsequent neuronal and vascular injury. In this article, we discuss the role of novel cellular pathways that are invoked during oxidative stress and may potentially mediate apoptotic injury in Alzheimer's disease. Ultimately, targeting new avenues for the development of therapeutic strategies linked to mechanisms that involve inflammatory microglial activation, cellular metabolism, cell-cycle regulation, G-protein regulated receptors, and cytokine modulation may provide fruitful gains for both the prevention and treatment of Alzheimer's disease.

Fig. (1). Pathways that originate with Wnt and Akt in Alzheimer's disease

Wnt and Akt can block activity of glycogen synthase kinase-3 β (GSK-3β). When active, GSK-3β phosphorylates tau protein facilitating the formation of neurofibrillary tangles. GSK-3β also phosphorylates (P) β-catenin leading to its degradation and subsequent induction of apoptosis. Akt inhibits GSK-3β through phosphorylation and also phosphorylates tau protein at the site of Ser²¹⁴ to prevent formation of neurofibrillary tangles. Wnt activates Akt directly or through Wnt-1 induced secreted protein (WISP-1). The phosphorylation and inactivation of GSK-3β by Wnt may occur through protein kinase C (PKC) or through Akt activation.

Fig. (2). Pathways of caspase activation during Alzheimer's disease

Caspase activation during Alzheimer's disease results in the cleavage of presenilin leading to apoptosis with loss of β-catenin, poly(ADP-ribose)polymerase (PARP), and Bcl-2. Caspases can cleave amyloid precursor protein (APP) and the resulting C-terminal fragment C31 resulting in hyperphosphorylation of tau protein (p-tau) as well as activation of glycogen synthase kinase-3β (GSK-3β). C31 and β-amyloid (Aβ) promotes the activation of caspases. Caspases also directly cleave tau protein to contribute to the formation of neurofibrillary tangles.

Fig. (3)

Erythropoietin (EPO) prevents DNA fragmentation during β-amyloid (Aβ) application in human neuroblastoma SH-SY5Y cells. Representative images illustrate DNA fragmentation with terminal deoxynucleotidyl transferase nick end labeling (TUNEL) in SH-SY5Y cells 24 hours after administration of Aβ (20 μM). Significant DNA fragmentation in SH-SY5Y cells is illustrated following Aβ treatment. In contrast, application of EPO (10 ng/ml) 1 hour prior to Aβ administration resulted in a significant reduction in DNA fragmentation when assessed 24 hours later.