Alzheimer's Disease: Treatment Strategies and Their Limitations

Abstract

Alzheimer's disease (AD) is the most frequent case of neurodegenerative disease and is becoming a major public health problem all over the world. Many therapeutic strategies have been explored for several decades; however, there is still no curative treatment, and the priority remains prevention. In this review, we present an update on the clinical and physiological phase of the AD spectrum, modifiable and non-modifiable risk factors for AD treatment with a focus on prevention strategies, then research models used in AD, followed by a discussion of treatment limitations. The prevention methods can significantly slow AD evolution and are currently the best strategy possible before the advanced stages of the disease. Indeed, current drug treatments have only symptomatic effects, and disease-modifying treatments are not yet available. Drug delivery to the central nervous system remains a complex process and represents a challenge for developing therapeutic and preventive strategies. Studies are underway to test new techniques to facilitate the bioavailability of molecules to the brain. After a deep study of the literature, we find the use of soft nanoparticles, in particular nanoliposomes and exosomes, as an innovative approach for preventive and therapeutic strategies in reducing the risk of AD and solving problems of brain bioavailability. Studies show the promising role of nanoliposomes and exosomes as smart drug delivery systems able to penetrate the blood-brain barrier and target brain tissues. Finally, the different drug administration techniques for neurological disorders are discussed. One of the promising therapeutic methods is the intranasal administration strategy which should be used for preclinical and clinical studies of neurodegenerative diseases.

Keywords: Alzheimer’s disease; blood–brain-barrier; exosomes; intranasal administration; liposomes; polyunsaturated fatty acids; therapeutics strategies.

Figure 1

Alzheimer’s Disease spectrum. (A) Key players in the pathogenesis of Alzheimer’s disease (AD). Reprinted with permission from [12]. Copyright 2009, Nature Publishing Group. (B) Aging and metabolic diseases alteration of brain metabolism, which progressively causes AD. Reprinted from [65], Copyright 2017, Yonsei University College of Medicine. (C) Differential diagnosis of AD using neuroimaging biomarkers. Reprinted with permission [66]. Copyright 2009, Elsevier.

Figure 2

3D in vitro models of Alzheimer’s disease. (A) PLGA scaffold encapsulating iPSC-derived NPCs, shown by proliferation marker Ki67, undifferentiated cell marker Nestin, and neural differentiation marker TuJ1. (i–iii) Cross-section ofthe 3D microfiber scaffold showing cell infiltration, distribution and differentiation. (iv,v) cell proliferation and differentiation. (vi) SEM image of the scaffold cross-section. Reprinted with permission from [134]. Copyright 2020, The Royal Society of Chemistry. (B) Reduction of neural plasticity in neural stem cells as a result of Aβ plaques. Image (i,iii) indicate healthy neural stem cells, which can form new synaptic connections, shown in (iii). Image (ii,iv) have the Aβ plaques incorporated in the hydrogel and are unable to form new synaptic connections. Reprinted with permission from [135]. Copyright 2018, Elsevier. (C) 3D spheroids derived from human neural progenitor cells, displaying Aβ pathology (shown in blue). Green and Red channels depict the neuronal cells and differentiated neurons, respectively. Reprinted from [138]. Copyright 2020, Nature Portfolio. (D) Acoustofluidic platform to assemble cells and Aβ oligomers into neuro-spheroids representing AD. Reproduced with permission of The Royal Society of Chemistry [139]. (i) cross-section of the 3D microfiber scaffold after sectioning (dotted line indicates the top surface of the 3D scaffold); (ii,iii) cell infiltration, distribution and differentiation of iPSC-derived NPCs (8529 cell line) inside the 3D scaffold as assessed via staining for TuJ1 (green) and Nestin (red) markers on D13; (iv) cell proliferation assessed by the Ki67 (green) marker and (v) cell differentiation with neurite formation indicated by the TuJ1 (red) marker of hESC-derived NPCs on D13; nuclei were counterstained with DAPI (blue); (vi) SEM image of the scaffold cross-section showing cell morphology and attachment on microfibers at 2000× magnification.

Figure 3

Schematic representation of liposomes, inorganic and polymeric nanoparticles crossing the BBB. Created with BioRender.com.