Overview of Alzheimer's Disease and Some Therapeutic Approaches Targeting Aβ by Using Several Synthetic and Herbal Compounds

Abstract

Alzheimer's disease (AD) is a complex age-related neurodegenerative disease. In this review, we carefully detail amyloid-β metabolism and its role in AD. We also consider the various genetic animal models used to evaluate therapeutics. Finally, we consider the role of synthetic and plant-based compounds in therapeutics.

Figure 1

Showing different causal and risk factors for Alzheimer's disease.

Figure 2

The amyloid cascade hypothesis of Alzheimer's disease. This hypothesis represents the classic theory of the origins of AD. Both familial forms of Alzheimer's (fAD) and later-onset forms with no known etiology (sporadic AD) lead to the production of excess Aβ ₄₂. Once this toxic peptide begins to aggregate, a cascade of events is triggered that produces the biological and neurological symptoms of Alzheimer's disease.

Figure 3

Processing of the amyloid-β protein precursor (AβPP) occurs by two pathways. (a) Nonamyloidogenic processing of AβPP involving action of α-secretase followed by γ-secretase as shown in the figure. (b) Amyloidogenic processing of AβPP involving β-secretase followed by the action of γ-secretase. Both processes generate soluble ectodomains (AβPPs_α and AβPPs_β) and a similar intracellular C-terminal fragment (AICD). The Aβ peptide starts within the ectodomain and continues into the transmembrane region (red). Adapted from Thinakaran and Koo [8].

Figure 4

A model showing Aβ ₄₂ oligomerization and fibrillization: the equilibrium between monomer to paranuclei and from paranuclei to large oligomers is rapid and reversible. The conversion of oligomers to protofibrils is slower but also reversible. Conversion of protofibrils into fibrils is an irreversible step. Basically, the monomers, paranuclei, and large oligomers do not have any definite structure instead of some β-turn/β-sheet and helical (α) elements. Essential conformational changes occur during protofibril formation where the unstructured, α-helix, and β-strand elements transform into β-sheet/β-turn structures.

Figure 5

(a) Sequence of Aβ ₄₂ that is derived from human AβPP. (b) Structural constraints in Aβ ₄₀ and Aβ ₄₂ fibrils. NMR measurements of Aβ ₄₀ fibrils have shown that residues 1–10 are unstructured and residues 11–40 adopt a β-turn-β fold. Side chain packing is observed between Phe19 and Ile32, Leu34 and Val36, Gln15 and Val36, and His13 and Val40 (orange dashed line). In Aβ ₄₂ fibrils, residues 1–17 may be unstructured (in black), with residues 18–42 forming a β-turn-β fold. Molecular contacts have been reported within the monomer unit of Aβ ₄₂ fibrils between Phe19 and Gly38 (blue dashed line) and between Met35 and Ala42 (black dashed line). In both Aβ ₄₀ and Aβ ₄₂, the turn conformation is stabilized by hydrophobic interactions (red residues) and by a salt bridge between Asp23 and Lys28 (purple dashed line).

Figure 6

Different therapeutic approaches for the treatment of AD.

Figure 7

(a) Proposed model for AD pathology based on abnormal metal interaction. Cu and Fe levels increase during aging in the CNS and result in increase in metal and Aβ interaction. Cu binding to Aβ results in ROS production and autooxidation of Aβ peptide. Oxidized Aβ contributes to synaptic pathology and plaque formation. Metals may also promote phosphorylation of tau and hence enhance formation of NFT which further contribute to AD pathology. (b) Model showing the amyloid-copper interaction. Notice the coordination sites at His 6 from one peptide together with His13 and His14 from the second peptide.

Figure 8

Illustration of the different components present in Aloe vera.

Figure 9

Figure showing the medicinal properties of Aloe vera.