Current experimental therapy for Alzheimer's disease

Abstract

In the past decade, enormous efforts have been devoted to understand the genetics and molecular pathogenesis of Alzheimer's disease (AD), which has been transferred into extensive experimental approaches aimed at reversing disease progression. The trend in future AD therapy has been shifted from traditional anti-acetylcholinesterase treatment to multiple mechanisms-based therapy targeting amyloid plaques formation and amyloid peptides (Abeta)-mediated cytotoxicity, and neurofibrillary tangles generation. This review will cover current experimental studies with the focus on secretases-based drug development, immunotherapy, and anti-neurofibrillary tangles intervention. The outcome of these on-going studies may provide high hope that AD can be cured in the future.

Keywords: Alzheimer’s disease; Experimental approach; amyloid plaque; gene therapy; immunotherapy; neurofibrillary tangles; secretase; small interfering molecule.

Fig. (1)

Processing of amyloid precursor protein (APP) and potential therapeutic targets. APP proteolysis undergo two different ways which include hydrolysis catalysed by α-secretase, resulting in release of soluble α-APPs, and the intra-membrane proteolysis catalysed by γ-secretase and produce peptides P3. The second pathway involves β-secretase catalyse which produce β-APPs and Aβ peptides, which ranging in length from 40 to 42 amino acids. Aβ42 peptide is prone to aggregation and formation of amyloid plaques lead to cell degeneration. Promote activation of α-secretase (B) as well as inhibit β-secretase (A) and γ-secretase (C) are promising targets. Immunotherapies use vaccine or Aβ specific antibodies to promote amyloid plaques degradation (D) have been shown safe and effective in animal models. Anti-microglia activation (NSAID) (E) Anti-apoptotic approaches and mitochondrial dysfunciton (F), and anti-oxidative stress agents (G) are benefit in blocking degeneration process.

Fig. (2)

Tau phosphorylation procedures and related target site. Deposition of extracellular Aβ may lead to activation of GSK3 β pathway and calpain-mediated pathway includes generation of P25 from P35 that results in formation of P25 and CDK5 complex. However, the complex plays an important role in transforming tau to hyperphosphorylated tau. Develop specific GSK3β inhibitor, CD5K inhibitor and MT-stabilizing drugs may attenuate the formation of hyperphosphorylated tau that would benefit for AD.

Fig. (3)

Proposed schematic model for the dual effects of ladostigil: neuroprotection and regulation/processing of holo-APP [Replicated from Yogev-Falach, M., et al., (2006) FASEB].