A multitude of signaling pathways associated with Alzheimer's disease and their roles in AD pathogenesis and therapy

Abstract

The exact molecular mechanisms associated with Alzheimer's disease (AD) pathology continue to represent a mystery. In the past decades, comprehensive data were generated on the involvement of different signaling pathways in the AD pathogenesis. However, the utilization of signaling pathways as potential targets for the development of drugs against AD is rather limited due to the immense complexity of the brain and intricate molecular links between these pathways. Therefore, finding a correlation and cross-talk between these signaling pathways and establishing different therapeutic targets within and between those pathways are needed for better understanding of the biological events responsible for the AD-related neurodegeneration. For example, autophagy is a conservative cellular process that shows link with many other AD-related pathways and is crucial for maintenance of the correct cellular balance by degrading AD-associated pathogenic proteins. Considering the central role of autophagy in AD and its interplay with many other pathways, the finest therapeutic strategy to fight against AD is the use of autophagy as a target. As an essential step in this direction, this comprehensive review represents recent findings on the individual AD-related signaling pathways, describes key features of these pathways and their cross-talk with autophagy, represents current drug development, and introduces some of the multitarget beneficial approaches and strategies for the therapeutic intervention of AD.

Keywords: Alzheimer's diesase; amyloid β; autophagy; neurofibrillary tangle; senile plaque; signaling pathways; tau.

Figure 1:. As an example, schematic representation of healthy and pathogenic signaling in AD;

(A) Ubiquitin proteasome system. Left panel shows healthy UPS. Misfolded proteins and protein (Aβ and Tau) aggregates are degraded by 26S proteasome with the help of ubiquitinating (E1, E2, and E3) and deubiquitinating enzymes (DUBs) in ATP-dependent manner. Right panel shows pathogenic UPS in AD. Impaired proteasomal function leads to inhibition of the misfolded proteins and aggregated Aβ and Tau degradation. This leads to accumulation of Aβ and Tau aggregates in neurons, nerve cell death, and finally AD pathogenesis. Enhanced level of mutant UBB+1, Aβ40/42 oligomers and/fibrils, Tau aggregates, mutation in E1 and E2 enzymes, reduced E3 ligase/CHIP and UCHL1 are responsible for aberrant UPS. Use of proteasome activators, aggregation inhibitors, and UCHL1 activators may provide management of AD. (B) Autophagy. Left panel shows healthy autophagy. Beclin 1, LC3-II, ULK1 complex, and Atg5-Atg12/Atg16L1 complex are involved in the formation of autophagosomes. Cytoplasmic contents such as protein aggregates (Aβ and Tau) and defective organelles are sequestered into a double-membrane-bound autophagosome. Further, these are transported and fuse with lysosomes in a Rab7- and SNARE-dependent manner. Aβ and Tau aggregates are then degraded by lysosomal hydrolases. Right panel shows defective autophagy in AD. Failure in autophagic process can be caused by protein aggregates, reduced expression of Beclin1, presenilin 1 dysfunction, disturbed lysosomal pH. Further, autophagic failure leads to accumulation of toxic proteins that subsequently affect cell health and survival. Finally, neurodegeneration affects cognitive function that leads to AD. Various drug targets and agents acting at different stages are shown in green color. The “→” refers to induction/activation and the “⊢” refers to inhibition. “↑” refers to increase and “↓” refers to decrease. Ub: Ubiquitin, DUBs: deubiquitinating enzymes, E1: Ub-activating enzyme, E2: Ub-conjugating enzyme, E3: Ub-ligase enzyme. mTOR: mammalian target of rapamycin; AMPK: AMP-dependent protein kinase; ROS: Reactive oxygen species; AVs: Autophagic vacuoles; ULK1: Unc-51 like autophagy activating kinase; Atg: Autophagy-related protein; SNAREs: Soluble NSF attachment protein receptor.

Figure 2:. Distribution of drugs in clinical trials by signaling pathways in AD;

Numerous drugs are in different phases of clinical trials that targeting different signaling pathways. Few drugs have targets in more than one pathway. Most of the drugs (38 drugs) have been targeted against Aβ signaling. In addition, some drugs are in the miscellaneous category with an unknown mechanism of action/undisclosed information.