Abstract and Introduction
Purpose of Review Stem cell therapy has the potential to modify the disease of Alzheimer's disease. This article aims to describe the mechanisms of action, preclinical animal studies, human clinical trials, and challenges for the future direction of stem cell therapy for Alzheimer's disease.
Recent findings Stem cells of diverse origins (embryonic, placental or umbilical cord blood, and induced pluripotent stem cells) and cell types (neural and mesenchymal stem cells) are widely studied in both animals and humans.
Summary In terms of mechanism of actions, recent research focused on the interplay between amyloid-beta Aβ (and tau), neurons, and glia. Stem cells can induce direct regeneration of neurons and synapses. They can also prevent activation of pro-inflammatory microglia, promote activation of anti-inflammatory microglia, inhibit astrogliosis, and promote nonreactive astrocytes. These effects in return may increase amyloid-beta (Aβ) degradation, decrease the risk of the Aβ cascade, repair injured neurons, and enhance synaptogenesis. Two completed and nine ongoing clinical trials using diverse stem cells and administration methods (intravenous, subcutaneous, and intra-cranial) were found for the treatment of Alzheimer's disease. Although stem cell therapy shows great potential to become a prospective treatment for Alzheimer's disease in the future, these studies are still in their early stages and more studies showing safety and efficacy are needed.
Dementia is a neurodegenerative, debilitating, and fatal disorder characterized by progressive cognitive impairment, behavioral disturbance, and loss of function of daily life. Alzheimer's disease is the most common cause of dementia, and account for 50~70% of all dementias worldwide. Alzheimer's Disease International reported that 50 million people worldwide are living with dementia in 2018, and with a new case occurring globally every 3 s, the disease is quickly becoming a fast pandemic with 152 million people by 2050.
Numerous hypotheses on the cause of Alzheimer's disease were proposed over the past several decades. The initial cholinergic hypothesis and neuromodulation theory proposed that Alzheimer's disease was caused by reduced synthesis of the neurotransmitter acetylcholine and excitotoxicity from glutamate accumulation, respectively.[3,4] These proposals led to successful development and Food and Drug Administration (FDA) approval of cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and a glutamatergic or N-methyl-D-aspartate receptor receptor antagonist (memantine). Unfortunately, none of these agents have disease-modifying potential, and their effects are limited only to symptom management. Therefore, the need for novel agents with different mechanisms of action and enhanced effectiveness is urgent and critical.
Over the past two and half decades, dementia research has focused on neuronal death caused by two proteins, plaques of extracellular amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles (NFTs) of abnormally hyperphosphorylated tau proteins.[6,7] However, drugs targeting these two proteins [such as β-secretase inhibitor (BACE-I) or γ-secretase inhibitor] either showed null results or clinical trials were halted because of low chance of success.[8,9] Results from antitau therapy (hydromethanesulfonate: LMTM) were equivocal; initial phase III trials showed negative results, but modified primary outcomes in an 18-month phase III trial suggested that LMTM might improve cognitive function in patients with Alzheimer's disease.[10,11] Neuroinflammation theory has received increasing attention in recent years, but disappointing results from clinical trials led to a decrease in pursuance of anti-inflammatory therapy in patients with Alzheimer's disease.[12–14] Inhibitory effects on microglia were postulated as an important reason for the failure of these anti-inflammatory drugs, and importance of targeting these glial cells were heightened. Increasing evidence suggests that novel stem cell techniques may enhance neurotransmission, promote neurogenesis and prevent or clear aversive proteins, and reduce neuroinflammation (Figure 1 summarizes history of the disease model of Alzheimer's disease with its therapeutic targets).
A brief history of the disease model of Alzheimer's disease with its therapeutic targets. Data from [14,15]. ACh, acetylcholine; BACE-I, b-secretase inhibitor; LMTM, hydromethanesulfonate (antitau therapy).
The purpose of this article is to review clinical and preclinical studies evaluating role of stem cells in treatment of patients with Alzheimer's disease. A recent review by Duncan and Valenzuela has thoroughly identified and summarized both animal studies and clinical. We first sought to further this study by elaborating possible mechanism of action of stem cells in the treatment of Alzheimer's disease mainly through integrating preclinical animal models. Second, its safety and efficacy in patients with Alzheimer's disease were investigated by systematically reviewing and updating all clinical trials available. Lastly, we critically discuss challenges and future directions of stem cells for treatment of Alzheimer's disease.
Curr Opin Psychiatry. 2019;32(2):105-116. © 2019 Lippincott Williams & Wilkins