Liposome delivery systems for the treatment of Alzheimer's disease

Abstract

Alzheimer's disease (AD) will affect around 115 million people worldwide by the year 2050. It is associated with the accumulation of misfolded and aggregated proteins (β-amyloid and tau) in the senile plaques and neurofibrillary tangles found in the brain. Currently available drugs for AD only temporarily alleviate symptoms and do not slow the inevitable progression of this disease. New drugs are required that act on key pathologies in order to arrest or reverse cognitive decline. However, there has been a spectacular failure rate in clinical trials of conventional small molecule drugs or biological agents. Targeted nanoliposomes represent a viable and promising drug delivery system for AD that have not yet reached clinical trials. They are biocompatible, highly flexible, and have the potential to carry many different types of therapeutic molecules across the blood-brain barrier (BBB) and into brain cells. They can be tailored to extend blood circulation time and can be directed against individual or multiple pathological targets. Modifications so far have included the use of brain-penetrating peptides, together with Aβ-targeting ligands, such as phosphatidic acid, curcumin, and a retro-inverted peptide that inhibits Aβ aggregation. Combining several modifications together into multifunctional liposomes is currently a research area of great interest. This review focuses on recent liposomal approaches to AD therapy, including mechanisms involved in facilitating their passage across the BBB, and the evaluation of new therapeutic agents for blocking Aβ and/or tau aggregation.

Keywords: amyloid; blood-brain barrier; cell-penetrating peptides; neurofibrillary tangles; senile plaques; tau.

Figure 1

Promising liposomal BBB transport mechanisms. Notes: Receptor-mediated transcytosis exploits receptors highly expressed at the BBB (eg, transferrin receptor). Receptor ligand binding triggers internalization and brain delivery. A relatively new mechanism, direct penetration, involves internalization primarily exhibited by CPPs (eg, TAT). Positively charged amino acids (+++) permit endocytosis by interacting with the negatively charged endothelial cell membrane (− − −). Once in the brain, multifunctional liposomes can be directed at an appropriate target (eg, at Aβ or tau) for AD therapy. Abbreviations: BBB, blood–brain barrier; CPPs, cell-penetrating peptides; Aβ, amyloid-β; AD, Alzheimer’s disease; TAT, transactivator of transcription of human immunodeficiency virus.

Figure 2

Promising liposomal modifications for AD therapy. Notes: These modifications improve their stability and bioavailability, aid BBB transportation, and engage therapeutic targets relevant to treatment of AD. Stability – (a) PEGylation. BBB transportation – (b) glutathione, (c) surface antibody, (d) PEG-peptide, (e) PEG-antibody, (f) lactoferrin, (g) glucose, (h) wheat germ agglutinin, (i) PEG-mApoE, (j) transferrin. Targeting systems for AD – (k) phosphatidic acid, (l) PEG-curcumin, (m) lipophilic peptide, (n) lipophilic drug, (o) hydrophilic peptide, (p) hydrophilic drug, (q) nucleic acid. Abbreviations: AD, Alzheimer’s disease; ApoE, apolipoprotein E; BBB, blood–brain barrier; PEG, polyethylene glycol.

Figure 3

The sink effect strategy. Notes: Aβ assemblies are in equilibrium between the brain and bloodstream, across the BBB endothelium. It is proposed that mApoE-PA modified liposomes sequester soluble Aβ (monomers or soluble oligomers) in the peripheral bloodstream, which is then cleared. This creates an imbalance of soluble Aβ. Transport of Aβ from the brain to the blood, across the BBB, is then favored, to restore this imbalance. This reduces Aβ burden in the brain and is coined the “sink effect.” Abbreviations: Aβ, amyloid-β; mApoE-PA, apolipoprotein-E-phosphatidic acid; BBB, blood–brain barrier.

Figure 4

Targeting strategy with PINPs. Notes: PINPs transport across the BBB by non-specific endocytosis, triggered by positively charged TAT interaction with the negatively charged membrane. RI-OR2-TAT inhibitor acts to prevent the aggregation of Aβ into oligomers and fibrils. Abbreviations: Aβ, amyloid-β; BBB, blood–brain barrier; PINPs, peptide inhibitor nanoparticles; TAT, transactivator of transcription of human immunodeficiency virus.

Figure 5

Incubation of PINPs with Aβ. Notes: Figure shows TEM images of negatively stained PINPs. (A) Individual PINPs before incubation with Aβ. (B) Individual PINPs after incubation with Aβ. (C) and (D) PINPs after extended incubation with Aβ bound to amyloid fibrils. Scale bars: A and B 150 nm, C and D 100 nm. Abbreviations: Aβ, amyloid-β; PINPs, peptide inhibitor nanoparticles; TEM, transmission electron microscope.

Figure 6

Cell survival and apoptotic pathway in AD therapy. Notes: Action of WGA-CRM-CL/LIPs: Curcumin inhibits phosphorylation of JNK and p38, preventing downstream phosphorylation of tau serine 202, leading to prevention of apoptotic neurodegeneration. NGF binds TrkA and mediates MAPK phosphorylation cascade and recruitment of CREB, enhancing overall cell survival. Abbreviations: CL, cardiolipin; CREB, cAMP response element binding protein; CRM, curcumin; JNK, c-Jun N-terminal kinase; LIPs, liposomes; MAPK, mitogen-activated protein kinase; NGF, neuronal growth factor; TrkA, tyrosine kinase receptor type-1; WGA, wheat germ agglutinin; AD, Alzheimer’s disease.