Current progress, challenges and future prospects of diagnostic and therapeutic interventions in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most prevalent, progressive and multifaceted neurodegenerative disorder associated with cognition, memory and behavioural impairments. There is no approved diagnosis or cure for AD, and it affects both developed and developing countries and causes a significant social and economic burden. Extracellular senile plaques of amyloid beta (Aβ) and intracellular neurofibrillary tangles of phosphorylated Tau (pTau) in the brain are considered to be the pathophysiological hallmarks of AD. In an attempt to explain the complexity and multifactorial nature of AD, various hypotheses (Aβ aggregation, Tau aggregation, metal dyshomeostasis, oxidative stress, cholinergic dysfunction, inflammation and downregulation of autophagy) based on pathophysiological changes that occur during the onset and progression of AD have been proposed. However, none of the hypotheses is capable of independently explaining the pathological conditions observed in AD. The complex and multifaceted pathophysiological nature of AD has hampered the identification and validation of effective biomarkers for early diagnosis and the development of disease-modifying therapies. Nevertheless, the amyloid hypothesis is the most widely accepted and is closely correlated with disease symptoms of AD that encompass all the disease hypotheses. Therefore, amyloid plaques are ideal biomarkers for the development of an early diagnosis of AD. Similarly, the formation of amyloid plaques can also serve as a target for the design of therapeutic tools via an inclusive approach that considers multiple disease pathways involved in AD. Our review article briefly introduces pathophysiological factors involved in AD using interdependent but diverse hypotheses. Recent advances in the development of effective molecular tools and techniques for diagnostic and therapeutic interventions in AD, especially those in the advanced stages (clinical trials) of development, are given special consideration. In addition, contributions from our laboratory to the development of selective molecular tools for diagnostic and therapeutic interventions that target multifaceted toxicity in AD are also covered. In summary, we discuss diverse aspects of molecular mechanisms that underlie the pathogenesis of multifactorial AD, current progress and possible bottlenecks that have hampered the development of early diagnostic tools and effective drugs. Challenges and future prospects include the integration of various disease pathways for the successful development of an early diagnosis and effective drugs for the treatment of AD.

Fig. 1. (a) Characteristic features of the pathology of AD in the human brain and recent statistics showing the dramatic and rapid rise of AD as a global epidemic. (b) Multiple pathological pathways of AD.

Fig. 2. Molecular tools and techniques available for the detection of biomarkers in AD.

Fig. 3. Red and NIR (far-red) fluorescent probes for diagnosis of AD. (a) Absorption and emission (λ_ex = 537 nm) spectra of the probe TC in the presence and absence (dotted lines) of Aβ42 fibrillar aggregates. Inset: molecular structure of TC. (b) Photographs of TC and samples of TC + Aβ42 fibrillar aggregates illuminated with visible and UV light (365 nm) and TC + Aβ42 fibrillar aggregates illuminated with a green laser (532 nm), which gives a red beam in the sample solution. (c) Normalized fluorescence intensity (NFI) of CQ upon interaction with various protein aggregates, biomacromolecules and polymorphic Aβ species. (d) Dual staining of human brain cross-sections using CQ and ThT (100 nM CQ: 1.57 mM thioflavin T). (e) CQ stains Aβ plaques and congophilic angiopathy in human brain tissue with Congo red as control. (f) Molecular structure of the probe CQ and selective staining of Aβ plaques in human brain tissue. CQ selectively stains Aβ plaques in brain tissue in AD even in the presence of NFTs of Tau. This figure has been adapted from ref. 49 and 50 with permission from Nature Publishing Group and Elsevier, respectively.

Fig. 4. Molecular structures of thioflavin T, thioflavin S, PET probes and SPECT probe for the detection and imaging of Aβ and Tau aggregates.

Fig. 5. Aggregation inhibitors based on small molecules and natural products.

Fig. 6. Peptidomimetic modulators. Cyclic hybrid peptoids (a) as autophagy modulators (b). (c) Schematic representation of inhibition and dissolution of Aβ42 aggregates by the peptidomimetic inhibitor P5. (d) Structure of P5. (e) Growth curve of yeast (autophagy model) with Aβ toxicity. P5 rescues yeast cells from Aβ toxicity. (f) Degradation of toxic GFP-βA by P5 in a WT GFP-βA yeast model. This figure has been adapted from ref. 88 and 89 with permission from Wiley and Nature Publishing Group, respectively.

Fig. 7. Multifunctional peptidomimetic modulators. (a) Schematic representation showing modulation of the multifaceted toxicity of Aβ by the multifunctional modulator P6. (b) Molecular structure of P6. (c) P6 rescues plasmid DNA (pBR322) from damage by ROS generated by the Aβ42 + Cu^II + Asc system. (d) P6 rescues PC12 cells from toxicity induced by metal-induced Aβ42 aggregates. This figure has been adapted from ref. 98 with permission from the American Chemical Society.

Fig. 8. (a) Small-molecule-based metal chelators and hybrid multifunctional modulators (HMMs). (b) Schematic representation of inhibition of the multifaceted toxicity of Aβ and mitochondrial damage by an HMM. (c) Molecular structure of an HMM (TGR 86). (d) TGR86 rescues PC12 cells from toxicity induced by metal-induced Aβ42 aggregates. TGR86 rescues the mitochondrial membrane potential of PC12 cells from the metal-induced toxicity of Aβ42. (e) Microscopic images and (f) quantification of fluorescence at 540 nm (λ_ex = 511 nm). This figure has been adapted from ref. 105 with permission from the American Chemical Society.

Fig. 9. (a) Active and passive immunotherapy. (b) Liposome-based active immunisation and interaction of anti-Aβ antibodies with Aβ. This figure has been adapted from ref. 120, 123 and 124 with permission from Nature Publishing Group (120 and 124) and BioMed Central (123).

Fig. 10. Molecular structures of inhibitors of β-secretase, γ-secretase and kinases that are undergoing clinical trials.

Fig. 11. Molecular structures of modulators of inflammation that are undergoing clinical trials.

Fig. 12. (a) Cholinergic inhibitors and NMDA antagonist for treating AD. Molecular docking of donepezil (b) and memantine (c) with AChE and NMDA receptors, respectively. This figure has been adapted from ref. 156 with permission from Nature Publishing Group.