Alzheimer's disease (AD) is an age-related pathological condition that accounts for up to 70% of all diagnosed cases of dementia. The disease is characterized by a progressive decline in cognitive abilities and affects memory, and learning. On the cellular level, it is characterized by degeneration and loss of cholinergic neurons in the hippocampus, entorhinal cortex, and basal forebrain. Pathological analysis of AD patient brains reveals extensive accumulation of amyloid beta (Aβ) plaques, tau protein hyperphosphorylation, and neurofibrillary tangles of neuronal extensions.
AD therapeutic strategies aim to eliminate the main pathological hallmarks of the disease: extracellular amyloid plaque and intracellular neurofibrillary tangle formation, loss of neural cells and synapses, and neuroinflammation. In order to achieve these objectives, several cell types were tested in research and pre-clinical studies, including bone marrow-derived mesenchymal stem cells (BM-MSCs), umbilical cord-derived mesenchymal stem cells (UC-MSCs) and neural stem cells (NSCs).
Mesenchymal stem cells (MSCs) can be easily isolated from different tissues of the body and cultured in-vitro. The ability to isolate them from the patient's own tissues, thereby circumventing risk of immune rejection, renders them ideal candidates for cell therapy. MSCs support neuronal protection by the secretion of neurotrophic factors such as, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and neurotrophic-3 (NT-3). In addition, MSCs secrete anti-inflammatory factors, regulate microglial activation, and inhibit the function of immune cells. Transplantation of BM-MSCs and UC-MSCs into the brains of AD animal models resulted in reduced Aβ plaques deposition, decreased tau hyperphosphorylation, restored microglial function, and elevated activated microglia. In addition, transplantation of UC-MSCs restored both learning and memory in AD mice.
Neural stem cells (NSCs) are multipotent, self-renewable cells residing within the nervous system. They can be isolated from adult or fetal nervous system tissues, cultured in-vitro, either as neurospheres or in a cell layer, and can be further differentiated into mature neuronal cells. In the adult brain, NSCs are found at the subventricular zone (SVZ) of the lateral ventricles, and in the subgranular zone of the hippocampal dentate gyrus. In addition, NSCs can also be found in the spinal cord and in the olfactory epithelium. NSC-based therapy for AD aims to promote cell replacement by differentiation in-vivo of the transplanted NSCs, and to promote neural recovery and protection via their secretion of various neuronal growth factors. When transplanted into AD animal models brains, NSCs differentiated into cholinergic neurons, astrocytes, and oligodendrocytes. In addition, injection of NSCs was shown to improve spatial learning and memory.
Ongoing clinical trials are assessing the potential of NSCs and UC-MSCs to treat Alzheimer's disease.