Stem Cell-based Therapeutic and Diagnostic Approaches in Alzheimer's Disease

Abstract

Background: Alzheimer's disease (AD) is a neurodegenerative impairment mainly recognized by memory loss and cognitive deficits. However, the current therapies against AD are mostly limited to palliative medications, prompting researchers to investigate more efficient therapeutic approaches for AD, such as stem cell therapy. Recent evidence has proposed that extensive neuronal and synaptic loss and altered adult neurogenesis, which is perceived pivotal in terms of plasticity and network maintenance, occurs early in the course of AD, which exacerbates neuronal vulnerability to AD. Thus, regeneration and replenishing the depleted neuronal networks by strengthening the endogenous repair mechanisms or exogenous stem cells and their cargoes is a rational therapeutic approach. Currently, several stem cell-based therapies as well as stem cell products like exosomes, have shown promising results in the early diagnosis of AD.

Objective: This review begins with a comparison between AD and normal aging pathophysiology and a discussion on open questions in the field. Next, summarizing the current stem cell-based therapeutic and diagnostic approaches, we declare the advantages and disadvantages of each method. Also, we comprehensively evaluate the human clinical trials of stem cell therapies for AD.

Methodology: Peer-reviewed reports were extracted through Embase, PubMed, and Google Scholar until 2021.

Results: With several ongoing clinical trials, stem cells and their derivatives (e.g., exosomes) are an emerging and encouraging field in diagnosing and treating neurodegenerative diseases. Although stem cell therapies have been successful in animal models, numerous clinical trials in AD patients have yielded unpromising results, which we will further discuss.

Keywords: Alzheimer's disease; Neurodegenerative diseases; aging; clinical trial; exosomes; stem cell therapy.

Fig. (1)

Endogenous repair in Alzheimer's disease; Some drugs and growth factors have treating effects on patients with Alzheimer’s disease (AD). These drugs can be administrated in different ways, including oral, nasal, injected intracranial (IC), subcutaneous (SC), and intravenous (IV). A) These neurotrophic drugs or substances can affect the sub-ventricular zone and dentate gyrus (DG), leading to neurogenesis and neural stem cell (NSC) proliferation and differentiation. B) Administration of these substances induces microglia migration, leading to amyloid β (Aβ) clearance. C) Moreover, administration of these factors enhances synapse formation by protecting cholinergic neurons and neurovascular remodeling. Stem cells (SCs) migration from bone marrow (BM) can also be triggered following the administration of these factors.

Fig. (2)

Exosome biogenesis: Exosomes originate from ILVs in MVBs (i.e., LE), which are generated by early endosomes. Either ESCRT-dependent or ESCRT-independent pathways modulate exosome biogenesis. In the ESRCT dependent pathway, (I) ESRT-0 sequesters ubiquitinated proteins into the endosomal domain, and (II) ESCRT-I and -II induce membrane budding, and (III) recruit ESCRT-III, which finally drives vesicle neck scission. (IV) After ILVs formation, ESCRT-III is separated from the MVB. However, in the ESCRT-independent pathway, exosomes and ILVs are generated by converting sphingomyelin to ceramide mediated by the sphingomyelinase enzyme on the endosomal membrane. Then, ceramide accumulation induces microdomain coalescence and triggers ILV formation. ILVs finally (1) fuse with the plasma membrane to form exosomes or (2) are degraded by lysosomes, or (3) are transported to the TGN for endosome recycling. Once exosomes reach their destination in the extracellular space, they may (4) fuse into the plasma membrane of the recipient cell and release their contents directly to the cytosol, or (5) be taken up by the target cell’s endocytic pathway and delivered back via a back-fusion event.