Abstract
Alzheimer's disease (AD) is the most common form of senile dementia worldwide and is a progressive and irreversible neurodegenerative disorder, which represents a huge socioeconomic burden on modern healthcare systems. The neuropathology of AD is characterised by a very complex, interconnected cascade of cellular events including the extracellular accumulation of neurotoxic amyloid-beta (Aβ) peptides in senile plaques, the intracellular aggregation of hyperphosphorylated tau protein in neurofibrillary tangles (NFTs), chronic neuroinflammation, severe oxidative damage, cholinergic deficits and synaptic collapse. Standard FDA approved therapies provide modest symptomatic relief, leading to intensive research into multi-target disease modifying natural compounds. Curcumin is a natural hydrophobic diarylheptanoid polyphenol isolated from the rhizome of the turmeric plant (Curcuma longa) and has been proposed as a promising multi-target therapeutic candidate due to its strong antioxidant, anti-inflammatory, anti-protein-aggregating and neurogenic activities. Preclinical studies have demonstrated that curcumin can modulate a variety of pathological pathways. Curcumin down-regulates BACE1 expression and alters APP processing; it binds directly to Aβ monomers and fibrils to inhibit their aggregation and to promote the disaggregation of plaques. Curcumin blocks kinases (such as GSK- 3β) to prevent tau hyperphosphorylation, increases Nrf2-mediated antioxidant enzyme expression, chelates transition metals, inhibits NF-κB-dependent chronic inflammatory cascades, and promotes adult hippocampal neurogenesis. However, the clinical translation of curcumin is severely hampered by the “bioavailability barrier” that is manifested by poor aqueous solubility, extensive first-pass metabolism in the intestine and liver, rapid systemic clearance and limited penetration across the blood-brain barrier (BBB). This review discusses multi-target neuroprotective mechanisms of curcumin, critically reviews the preclinical success and human clinical trial outcomes, and highlights advanced nano formulations (solid lipid nanoparticles, colloidal sub-micron dispersions, polymeric nanoparticles, multi-walled carbon nanotubes and exosomes) and synergistic combination regimens to maximise its CNS bioavailability and therapeutic efficacy in humans.