**3. Stem cell therapy for AD**

There are some theoretical approaches to treat early AD. One is to target upregulation of resident neural stem cells (NSCs) niches within the adult brain. In fact, this regulation is to stimulate the development of adult hippocampal nerve, which has reached the purpose of compensating the degenerated nerve. Adult hippocampal neurogenesis may play a key role in learning and memory, so promoting this endogenous process may help improve amnesia in patients with early AD. Another approach is to up-regulate growth factors that are known to modulate neurogenesis integrally, either through drug therapy or gene therapy or, as we describe in this paper, through stem cell therapy. This type of growth factor includes brain-derived neurotrophic factor (BDNF) [36, 37], insulin growth factor-1 (IGF-1) [38], nerve growth factor (NGF) [39–42], vascular endothelial growth factor (VEGF) [43, 44] and so on. Stem cell therapy aims to rescue cognitive function by introducing exogenous stem cells to restore degenerated neural networks. These stem cells can be used as cell delivery systems through the natural or induced production of neuroprotective growth factors utilizing the paracrine "bystander" mechanism. Alternatively, therapeutic recovery may occur through the differentiation and involvement of stem cells in refilling degenerated neuronal circuits. It's a finely balanced, complex, multi-step process.

Some of stem cells are now in clinical use, such as embryonic stem cells (ESCs) derived from the inner cell mass of preimplantation embryos and induced pluripotent stem cells (iPSCs) derived from the epiblast layer of implanted embryos [45, 46]. Mesenchymal stem cells (MSCs) can promote tissue repair through the secretion of extracellular vesicles that carry a variety of cytokines, growth factors and microRNAs (miRNAs) [47]. Adipose tissue-derived stem cells (ADSCs) are a replacement therapy for MSCs, with the similar mechanism which secretion extracellular vesicles (EVs) to multiple proteins possessing neuroprotective and neurogenesis activities [48]. NSCs participate extensively in mammalian brain homeostasis and repair and exhibit pleiotropic intrinsic properties which makes them a good method for the treatment of AD [49].

### **3.1 ESCs**

ESCs are cells isolated from early embryos or primitive gonads. It has the characteristics of infinite proliferation, self-renewal and multidirectional differentiation *in vitro* culture. Both *in vitro* and *in vivo*, ESCs can be induced to differentiate into almost all cell types in the body, so they can be used to improve the recovery of neurodegenerative diseases (such as AD). Therefore ESCs have a broad application prospect in autologous stem cell therapy [50, 51]. Thymic epithelial progenitor cells derived from mouse ESCs with deleted amyloid precursor protein gene have been proved to have the ability to alleviate AD symptoms [52]. Early human embryonic stem cells (hESCs)-derived neural populations consist of various embryonic neural progenitors (ENPs) with broad neural developmental propensity. The hESC-ENPenriched neural transcription factors (TFs) can directly transform human cells into ENP phenotypes. Induced ENPs (IENPs) and their derivatives summarize the

signature pathological characteristics of AD and hold promise for future strategies for disease modeling and clinical intervention [53].

Although ESCs are good candidates for AD cell therapy, they may bring some ethical and practical problems. Even if we overcome the problem of immune rejection, there have been reports of teratomas resulting from transplanted ESCs [54].
