Hypothesis: apo-lactoferrin-Galantamine Proteo-alkaloid Conjugate for Alzheimer's disease Intervention

Abstract

Alzheimer's disease (AD) is known to be caused by the accumulation of deformed beta amyloid and hyperphosphorylated tau proteins resulting into formation and aggregation of senile plaques and neurofibrillary tangles in the brain. Additionally, AD is associated with the accumulation of iron or metal ions in the brain which causes oxidative stress. Galantamine (Gal) is one of the therapeutic agents that has been approved for the treatment of AD, but still saddled with numerous side effects and could not address the issue of iron accumulation in the brain. The use of metal chelators to address the iron accumulation has not been successful due to toxicity and inability to address the aggregation of the plaques. We therefore hypothesize a combinatorial antioxidant-metal-chelator approach by formulating a single dosage form that has the ability to prevent the formation of free radicals, plaques and accumulation of iron in the brain. This can be achieved by conjugating Gal with apo-lactoferrin (ApoLf), a natural compound that has high binding affinity for iron, to form an apo-lactoferrin-galantamine proteo-alkaloid conjugate (ApoLf-Gal) as a single dosage form for AD management. The conjugation is achieved through self-assembly of ApoLf which results in encapsulation of Gal. ApoLf changes its conformational structure in the presence of iron; therefore, ApoLf-Gal is proposed to deliver Gal and pick up excess iron when in contact with iron. This strategy has the potential to proffer a dual neuroprotection and neurotherapeutic interventions for the management of AD.

Keywords: Alzheimer's disease; antioxidant; apo-lactoferrin; free radical; galantamine; metal chelation; proteo-alkaloid.

Figure 1

Schematic diagram of the synthesis, mechanism of release of galantamine and absorption of iron by ApoLf–Gal conjugate.

Figure 2

Schematic diagram demonstrating the potential neurorescue (neuroprotective–co‐neurotherapeutic) interventional mechanism of the ApoLf –galantamine conjugate.

Figure 3

Preliminary in silico molecular interaction analysis of galantamine with apo‐lactoferrin (PDB ID: 1CB6) and iron‐saturated lactoferrin (PDB ID: 1LFG). The most favourable pose of galantamine (pink molecule in sphere rendering) within (A) the apo‐lactoferrin casing (rainbow structure in ribbon rendering); and (B) the iron‐saturated lactoferrin casing (rainbow structure in ribbon rendering). The docking calculations were carried out using DockingServer with the aid of AutoDock tools.

Figure 4

Molecular docking data depicting the 2D plot showcasing the interacting side chains and bond lengths within (A) ApoLf/galantamine proteo‐alkaloid complex; and (B) iron‐saturated Lf/galantamine proteo‐alkaloid complex. The docking calculations were carried out using DockingServer with the aid of AutoDock tools.