Hypothesis: apo-lactoferrin–Galantamine Proteo-alkaloid
Conjugate for Alzheimer’s disease Intervention
Olufemi D. Akilo
, Pradeep Kumar
, Yahya E. Choonara, Priyamvada Pradeep,
Lisa C. du Toit, Viness Pillay *
Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic
Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
Received: August 7, 2017; Accepted: November 1, 2017
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 man-
agement of AD.
AD is the most common cause of dementia, which affect mostly
elderly people, and it is connected to the loss of cholinergic neurons
in parts of the brain . AD is one of the most severe neurodegenera-
tive disorders. Approximately 13% of people who are 65 years and
above are affected by this disorder in the United States alone  and
is the sixth leading cause of death for people age 65 years and above
. It is projected that by 2050, there will be almost one million new
cases per year. Furthermore, it is expected that there will be remark-
able increase in the number of people with AD who are 85 years and
above across all racial and ethnic groups. AD is characterized by loss
of memory in the patient wherein the patient ﬁnds it difﬁcult to
remember things that are learnt recently coupled with failure of
acquiring new information [4, 5]. The symptoms noticeable at the
early stage include difﬁculties in reasoning, effective planning, atten-
tiveness, as well as conceptual thinking. Episodic, semantic and
implicit memories are less affected than new facts and memories .
Progressively, the patient is unable to perform most common activi-
ties of daily living as speech, reading and writing difﬁculties set in.
The cause of AD is associated with genetic heritability  as well
as cholinergic , amyloid and tau hypotheses. However, it is widely
believed that advanced age is the major risk factor of AD. The genetic
factor is brought about by gene mutations on chromosome 21 in the
b-amyloid precursor protein (APP), which are responsible for early-
onset of AD in family that has history of the disease [9, 10]. Choliner-
gic hypothesis proposed that AD is caused as a result of reduction in
the synthesis of neurotransmitter acetylcholine . Protein misfold-
ing disease is a characteristic of AD caused by the accumulation of
deformed beta amyloid (Ab) which resulted into senile plaques and
also the accumulation of hyperphosphorylated tau proteins in the
brain resulting into formation of neuroﬁbrillary tangles. The aggrega-
tion and accumulation of these plaques and tangles in the brain have
become the most prominent culprits of AD [12–14].
Iron is extremely reactive and in high concentration can lead to
neuronal death . Iron known to be so important in the mammalian
Both authors contributed equally to this work.
*Correspondence to: Prof. Viness PILLAY
ª 2018 The Authors.
Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use,
distribution and reproduction in any medium, provided the original work is properly cited.
J. Cell. Mol. Med. Vol 22, No 3, 2018 pp. 1957-1963