Stem Cell Strategies for the Modeling and Therapy of Alzheimer’s Disease
Pp. 20-55 (36)
Alzheimer's disease (AD) is the most common form of dementia in aged
populations.AD is characterized by a progressive decline in memory and cognitive
function, accompanied with behavioral changes such as confusion, irritability and
aggression, mood swings, language breakdown and eventually long-term memory loss.
The most significantly pathological findings in the brains affected by AD are senile
plaques (SP), neurofibrillary tangles (NFT) and neuronal loss or degeneration,
particularly in the areas connected to the cerebral cortex and hippocampus.The most
prominence among these regions is the basal forebrain cholinergic neurons. Many AD
studies and clinical trials focus on inhibiting the formation of extracellular senile
plaques and intracellular neurofibrillary tangles to prevent or halt disease progression.
For example, the Food and Drug Association (FDA) has approved three acetylcholinesterase
inhibitors (AChEIs), donepezil, rivastigmine and galantamine as AD
therapy. Elevating the neurotransmitter acetylcholine by AChEIs has been shown to
benefit cognitive functions in patients. Excitotoxicity caused by glutamatergic synaptic
dysfunction contributes to cognitive AD symptoms. Another FDA-approved AD drug,
the N-methyl-D-aspartate (NMDA) receptor antagonist memantine, is thought to
alleviate the excitotoxicity. To date, however, none of these treatments have been
shown to be safe and effective in clinic. Stem cell therapy is a promising therapeutic
strategy, which has been shown to replace the neurodegenerative cholinergic neurons
and provide exogenous neurotrophic factors in AD brains. Stem cells have been used as
therapy of neurodegenerative diseases to deliver RNAi to the brains and regulate the
expression of neprilysin, an amyloid-β (Aβ)-degrading enzyme. More recently, stem
cells, especially induced pluripotent stem cells (IPSCs), have been used for AD
modeling and drug screening. However, effective drugs or other interventions that stop
or delay progression of AD remain elusive. Due to the multifaceted features of AD,
further investigations of AD therapies are necessary. This review will discuss the recent
progress of stem cell strategies for AD modeling and therapy.
Alzheimer’s disease, Drug discovery, Small molecules, Stem cells,
Department of Pediatrics, Northwestern University Feinberg School of Medicine, Lurie Children`s Hospital Research Center, Chicago, IL 60614, USA.