Megan Marcom

 Introduction: Alzheimer’s Disease (AD) is the most frequent type of dementia and neurodegeneration that occurs in middle to late life, and its prevalence is expected to double within 20 years as average lifespan increases.¹ Pathologically, AD is characterized by widespread synaptic and neuronal loss, inflammation, and two hallmark protein aggregates: plaques composed of beta-amyloid (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau. The accumulation of these protein aggregates interferes with many cellular functions, and contributes to the substantial loss of neurons and synapses in the hippocampus and cortex.² Though widespread, certain brain regions such as hippocampus, entorhinal cortex, and basal forebrain are more profoundly impacted in AD. These areas of the brain serve a crucial role in learning and memory. ² The sub-granular zone of the adult brain houses cell types of varying degrees of neuronal maturity and once they become dentate gyrus granule cell neurons, they integrate into hippocampal networks encoding spatial memory and pattern. Once mature, these cells are indifferent from the existing neurons of the dentate gyrus and will terminally differentiate into local interneurons and contribute to key olfactory functions, including olfactory response to chemical cues, olfactory memory, and conspecific interactions. ³ Methods. Since NSCs have the ability of self-renew, undergo multi-cellular differentiation and are endowed with destination to neural cells, they are ideal sources for cell therapies for AD. Novel research has shown SVZ of 5XFAD mice, an AD mouse model, has decreased neuronal development. ⁴ In one study, APP/PS1 transgenic mice were implanted with human NSCs to the bilateral hippocampus to assess effect on behavior and pathology of AD. Behavior field testing included open field testing for anxiety and maze testing for spatial memory learning. Pathological tests included Nissl staining for neuronal loss, and primary antibodies directed toward GFAP, microtubule proteins, and other cortical structures. ⁵ Results. Through secretion of neurotrophins, transplanted NSCs increase long term potentiation and promote long term neuronal survival, resulting in improved cognition and motor performance. ⁶ Encouragingly, studies demonstrate favorable survival, migration and differentiation of transplanted NSCs in the brain of AD mice. This may be related with the fact that the hippocampus was the targeted regions of these studies, which is related with neurogenesis and can provide appropriate microenvironment for engrafted NSCs. ⁵ Conclusions. Studies suggests that it is feasible to transplant NSCs in AD mice, providing preclinical evidence that NSC transplantation can be a choice for patients with AD. Cell rejection is an additional challenge to NSC transplantation therapy in xenogeneic transplants. Encouragingly, studies demonstrate favorable survival, migration and differentiation of transplanted NSCs in the brain of AD mice. ⁵

1. Han MH, Koh SH, Lee EH. Current Opinion on the Role of Neurogenesis in the Therapeutic Strategies for Alzheimer Disease, Parkinson Disease, and Ischemic Stroke; Considering Neuronal Voiding Function. Int Neurourol J. 2016 Dec 26; 20(4):276-287.
2. Andreeva, T.V., Lukiw, W.J. & Rogaev, E.I. Biochemistry Moscow (2017) 82: 122.
3. Zheng R, Zhang ZH, Chen C, Chen Y, Jia SZ, Liu Q, Ni JZ, Song GL. Selenomethionine promoted hippocampal neurogenesis via the PI3K-Akt-GSK3β-Wnt pathway in a mouse model of Alzheimer’s disease. Biochem Biophys Res Commun. 2017 Mar 25;485(1):6-15.
4. Park SE, Lee J, Chang EH, Kim JH, Sung JH, Na DL, Cang JW. Activin A secreted by human mesenchymal stem cells induces neuronal development and neurite outgrowth in an in vitro model of Alzheimer’s disease: neurogenesis induced by MSCs via activin A. Arch Pharm Res. 2016 Aug;39(8):1171-9.
5. Li X, Zhu H, Sun X, Zuo F, Lei J, Wang Z, Bao X, Wang R. Human Neural Stem Cell Transplantation Rescues Cognitive Defects in APP/PS1 Model of Alzheimer’s Disease by Enhancing Neuronal Connectivity and Metabolic Activity. Front Aging Neurosci. 2016 Nov 23; 8: 282.
6. Marei HE, Elnegiry AA, Zaghloul A, Althani A, Afifi N, Abd-Elmaksoud A, Farag A, Lashen S, Rezk S, Shouman Z, Cenciarelli C, Hasan A. Nanotubes Impregmented Human Olfactory Bulb Neural Stem Cells Promote Neuronal Differentiation in Trimethyltin-induced Neurodegeneration Rat Model. J Cell Physiol. 2017 Jan 25.