Flavonoids as Therapeutic Compounds Targeting Key Proteins Involved in Alzheimer’s Disease

Abstract

Alzheimer's disease is characterized by pathological aggregation of protein tau and amyloid-β peptides, both of which are considered to be toxic to neurons. Naturally occurring dietary flavonoids have received considerable attention as alternative candidates for Alzheimer's therapy taking into account their antiamyloidogenic, antioxidative, and anti-inflammatory properties. Experimental evidence supports the hypothesis that certain flavonoids may protect against Alzheimer's disease in part by interfering with the generation and assembly of amyloid-β peptides into neurotoxic oligomeric aggregates and also by reducing tau aggregation. Several mechanisms have been proposed for the ability of flavonoids to prevent the onset or to slow the progression of the disease. Some mechanisms include their interaction with important signaling pathways in the brain like the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways that regulate prosurvival transcription factors and gene expression. Other processes include the disruption of amyloid-β aggregation and alterations in amyloid precursor protein processing through the inhibition of β-secretase and/or activation of α-secretase, and inhibiting cyclin-dependent kinase-5 and glycogen synthase kinase-3β activation, preventing abnormal tau phosphorylation. The interaction of flavonoids with different signaling pathways put forward their therapeutic potential to prevent the onset and progression of Alzheimer's disease and to promote cognitive performance. Nevertheless, further studies are needed to give additional insight into the specific mechanisms by which flavonoids exert their potential neuroprotective actions in the brain of Alzheimer's disease patients. KEYWORDS: Flavonoids, Alzheimer's disease, amyloid precursor protein, amyloid beta, BACE-1, tau, signaling A lzheimer's disease (AD) is a neurodegenerative disorder and the most common form of dementia worldwide. The major histopathological hallmarks of AD include proteinous aggregates in the form of neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau 1,2 and extracellular senile plaques, which are deposits of heterogeneously sized small peptides of amyloid-β (Aβ) that are formed via sequential proteolytic cleavages of the amyloid precursor protein (APP) 3 (Figure 1). Dominant mutations in APP, presenilin-1 (PS1) or PS2 are responsible for the early onset or familial form of AD. These mutations have been shown to profoundly alter APP metabolism, favoring the production of aggregation-prone Aβ species, these findings formed the basis for the "amyloid cascade hypothesis" of AD pathogenesis. This broadly accepted hypothesis states that the generation of neurotoxic Aβ peptides by β-secretase and γ-secretase are at the basis of AD pathophysiology. Other hallmarks of this disease, like neurotransmitter changes 4,5 and neuronal and synapse loss in the neocortex and the hippocampus 6,7 develop as a consequence of this event.■ AMYLOID PRECURSOR PROTEIN APP belongs to a protein f...

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