Introduction

Alzheimer’s disease (AD) is one of the neurodegenerative diseases that recognized by a loss of memory and cognitive function. The disease continues to progress to Dementia, an irreversible loss of memory [1]. Normally, AD starts around the ages of 5565 or even older [2]. The familial gene-related early-onset of Alzheimer’s disease (EOAD) are found among people between 40 to 50 years old with a poor prognosis [3].

The molecular analysis of the disease shows an accumulation of aggregated amyloid-β (Aβ) protein and hyper-phosphorylated tau tangles. Both are known to interfere with signal transmission [4,5]. The two forms of Aβ peptide, Aβ 1–40, and Aβ 1–42, are associated with EOAD [6]. A transmembrane amyloid precursor protein (APP), which is present in neurons, produces soluble Aβ peptide after being cleaved of by β-secretase followed by γ-secretase, [7,8].

There are no cures for AD, however, different treatment strategies are being attempted to improve the AD symptoms or slow down the progression of the disease [9,10]. Some of the main approaches to treat AD patients are:

• Inhibition of cholinesterase activities.
• Inhibition of NMDA receptor mediated signal transduction.
• Immunotherapeutic degradation of Aβ and tau deposits [11,12,13].

These treatments though bring some relief to the patients with AD but are not a cure for the disease. Recently, a new approach with stem cells and gene-modified cells are being used in the therapeutic strategies for AD along with other neurodegenerative disorders like Parkinson’s disease. This review highlights the various types of stem cells therapies, gene therapies and genemodified cell therapies for potential treatments of AD.

Possible Therapies of AD

Small molecule inhibitors:

The most direct target in anti-Aβ therapy is the Inhibition of Aβ production. Various small molecule inhibitors of β- and γ-secretase enzymes can reduce the formation of β-amyloid plaques, however, cannot reverse the existing plaques or improve the impaired cognition [14,15,16,17,18,19,20,21,22].

The inhibition of the other target, tau protein, which forms the neurofibrillary tangles are being tested in phase I and II trials with small molecule inhibitors [23,24].

Gene Therapy:

Familial early-onset familial AD (EOAD) cases are related with the mutation of genes encoding PSEN1, PSEN2 and APP. Soluble Aβ-oligomers are also causing impaired synaptic and neuronal functions [25]. However, none of the transgenic mouse models that accumulate Aβ-oligomers and Aβ-plaques have reproduced the neurodegenerative pathologies. There are other proteins like hyper-phosphorylated tau, apolipoprotein E (APOE)associated lipid metabolism and inflammation that are linked to AD cases [26,27,28].

In animal study viral vector-mediated neurotrophic factors gene transfer can potentially halt the progression of neuro-degeneration in AD [31,32,33]. However, systemic injection of certain growth factors results in strong peripheral side effects, and most of the proteins do not cross the blood–brain barrier.

Cell therapy:

Thoughts of cell therapy for AD cases came from the achievement of doing replacement of the loss of DA-ergic neural cells by transplanting a functional neural cells in PD patients [34, 35]. Recently, it was shown that induced pluripotent stem cells (iPSCs) derived from astrocytes when transplanted into PD brain, turns into dopamine-producing cells inside there [36,37].

Since AD and PD at the their cellular and molecular level are more similar to each other [38], we believe cell replacement therapy for AD can also be done provided the right cell-type can be selected. However, in contrasts to PD, the possibilities in AD are a great challenge because of widespread pathological changes in their brain [39].

Here we will discuss, not only what cells but also why and how our strategic concept would be the best choice for AD cell-therapy. In order to achieve a successful cell-replacement therapy for AD, some important criteria are to be considered:

• Selection of cells whose growth potential and survival length is acceptable for having enough amount of cells for transplantation, but not a cancer cell.
• Should differentiate.
• Should have Axon extension ability.
• Should have ability to form functional synapses.
• Stable and long-term integration of the cells into the host brain circuitry.

Selection of cells

1. Embryonic Stem Cells (ESCs):

ESCs are derived from developing blastocyst, and they produce every type of cell and tissue in the body [40,41]. Transplantation of ESCs can possibly form teratomas or teratocarcinomas and shows immune rejection [42]. Nevertheless, ESCs after differentiation to neural stem cells (NSCs), mesenchymal stem cells (MSCs), or other types of cells can be used for cell replacement therapy.

2. Neural Stem Cells (NSCs):

NSCs produce neuroblasts that mature to neurons involved in the sense of smell, memory and other cognitive functions [43,44]. Therefore, the transplantation of NSCs in patients with AD signifies the use for cell replacement therapy [45]. Commercially available NSC lines (HB1.F3) have been explored for their efficacy using the PD and AD animal model [46,47,48], which showed promising improvement in their impaired cognitive function as well as their difficult movement [49]. Blurton-Jones et al. showed that NSCs transplanted into the hippocampus of aged triple transgenic mice (3xTg-AD) reversed their cognitive impairment [50]. We recently demonstrated that modification of commercially available NSCs by cell-cell interaction with human normal melanocytes increases the growth potential of NSCs and their ability to produce Dopamine, BDNF, GDNF, etc. in cell culture media [51]. In addition, NSCs can be differentiated into cholinergic neurons that are especially vulnerable in AD patients [52,53].

3. Mesenchymal Stem Cells (MSCs):

MSCs are multipotent cells that can differentiate into neuronal cells and glial cells both in vitro and in vivo [54,55]. MSCs can easily be grown in large numbers as well [56,57]. MSCs can also be used for autologous transplantation [58], which bypasses the need for immunosuppressant. Bone marrow-derived MSCs transplantation into the hippocampus of APP/PS1 mice has led to reduction in Aβ deposition and tau hyper-phosphorylation and showed an improvement in spatial learning and memory [59,60]. Similar results were also obtained when MSCs derived from human umbilical chord were transplanted into AD-mouse model [61,62].

4. Induced Pluripotent Stem Cells (iPSCs):

Yamanaka and Takahashi et. al. first showed that somatic cells could be transformed to induced pluripotent stem cells (iPSCs) by reprogramming with Klf4, Sox2, c-Myc, and Oct4 transcription factors [63]. In addition, similar results were documented with Nanog, and Lin28, too. [64,65].

5. Astrocytes:

Several studies have shown that there are large numbers of activated astrocytes and microglia around the Aβ plaques in AD patients [66,67,68]. This indicates the involvement of astrocytes and microglia in the clearance of Aβ deposits from the AD brain. Both cultured adult and neonatal mouse astrocytes showed Aβ clearance by phagocytosis [69]. Therefore, it appears that transplantation of astrocytes could be useful in AD treatment, also.

Gene-Modified Cell-Based Therapy for AD

Stem cells could be genetically modified to increase their growth rate and for longer survival time, but should differentiate [69]. These modified stem cells could also deliver several factors that can ameliorate neurological disorders [70].

Due to the loss of cholinergic neurotransmitters in AD, some researchers are interested in developing gene-modified cells that can produce acetylcholine (Ach). Primary fibroblast cells that are genetically engineered to express induced choline acetyltransferase have shown to produce acetylcholine (Ach) in the hippocampus of transplanted rats [71].

MSCs that overexpressed the Neprilysin (NEP) gene demonstrated the ability to degrade Aβ peptides in vitro [72]. Similar results were obtained when fibroblasts transfected with a lentivirus carrying NEP gene were transplanted into the transgenic mice [73].

Wu et al. [74] was showed that genetically modified NSCs expressing human nerve growth factor (hNGF) could integrate into host tissue and replace damaged or lost neuronal cells. Based on a phase I clinical trial, implantation of fibroblasts loaded with the hNGF gene into the forebrain of eight AD patients showed an impressive improvement in their cognitive impairment [75].

NSCs are also able to express several growth factors that can improve memory function in AD patients [76]. hNGF is one that can rescue cholinergic neurons in the rodent and primate brains and enhance cholinergic function of neurons in them [77,78]. Another growth factor, brain derived growth factor (BDNF) that is produced in brain, effects neuronal activity, their function, and survival [79]. Delivery of BDNF gene in mice and primates have reversed the loss of synapses, improved cell signaling and restored cognitive functions [80]. Furthermore, NSCs carrying transfected BDNF-gene exhibit higher efficacy in spatial learning and memory than NSCs alone [81].

Recently we have created a modified neural stem cell by cellcell interaction with normal human melanocytes, and the modified cells can survive for long time but differentiate, produce dopamine and BDNF/GDNF [82,83,84]. Our notion, therefore, is that the cell-replacement therapy of AD/PD/Dementia patients with a modified neural cells could be relevant and productive [84,85,86,87], however various challenges like immune rejection, availability of enough amount of cells, methodologies of transplantation of cells are still remain as unanswered. Intra-cranial deep-brain surgery (DBS) for delivery of cells is loaded with many risks. Therefore, the development of extra-cranial methods of cell delivery across the blood-brain barrier (BBB) may solve this issue and simplify the procedure [89,90].

Summary:

Many studies have been done to help aid AD patients yet there are no cures that can stop or reverse the progression of the AD pathology. Different stem cells have been used to study their efficacy against AD, which are showing promising results in both in vitro and in vivo studies. Cell-based therapy using stem cells or gene-modified cells offers several advantages such as direct targeting of the pathology by incorporating new cells to replace the existing nonfunctional or non-supportive cells. Clinical studies have started and have shown satisfactory results. However some practical challenges such as cell longevity and immune-tolerance added with surgical complicacy still needs to be considered.

Intra-cranial delivery includes brain surgery which has many risk factors, therefore the development of extra-cranial methods of cell delivery across the blood-brain barrier (BBB) may be warranted. Second, the best site for graft placement is another issue to be considered, and also should it be tailored to each patient’s separately. Further the methodology of cell transplantation is the another challenge in this therapeutic approach and should be carefully discussed. Finally, we need to consider the risk–benefit analysis of cell therapy for AD, as well.

Acknowledgment

We acknowledge all of our staff members, scientists from All Excel, Inc. to support during the writing of this review by providing materials, and editing. Thanks are due to Ms. Bethany Pond for editing the manuscript.

Authors Contribution

Both the authors contributed equally.

Conflict of Interest

The authors declare no conflict of interest, financial or otherwise.

References

1. Barten DM and Albright CF. (2008). Therapeutic strategies for Alzheimer’s disease. Mol Neurobiol 37:171–186.
2. Eby DW, Silverstein NM, Molnar LJ, Leblanc D and Adler G. (2012). Driving behaviors in early stage dementia: a study using in-vehicle technology. Accid Anal Prev 49:330–337.
3. Molsa PK, Marttila RJ and Rinne UK. (1986). Survival and cause of death in Alzheimer’s disease and multi-infarct dementia. Acta Neurol Scand 74:103–107.
4. Takata K and Kitamura Y. (2012). Molecular approaches to the treatment, prophylaxis, and diagnosis of Alzheimer’s disease: tangle formation, amyloid-beta, and microglia in Alzheimer’s disease. J Pharmacol Sci 118:331–337.
5. Davies CA, Mann DM, Sumpter PQ and Yates PO. (1987). A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer’s disease. J Neurol Sci 78:151–164.
6. Parameshwaran K, Sims C, Kanju P, Vaithianathan T, Shonesy BC, Dhanasekaran M, et. al. (2007). Amyloid beta-peptide Aβ (1–42) but not Aβ (1–40) attenuates synaptic AMPA receptor function. Synapse 6:367–374.
7. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, et al. (1999). Betasecretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286: 735–741.
8. Selkoe DJ. (1999). Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature 399:A23–A31.
9. Birks JS, Melzer D, and Beppu H. (2000). Donepezil for mild and moderate Alzheimer’s disease. Cochrane Database Syst Rev.
10. Muir KW. (2006). Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists. Curr. Pharmacol.  6:53–60.
11. Solomon B. (2002). Immunological approaches as therapy for Alzheimer’s disease. Exp. Opinion on Biol. 8:907–917.
12. Yoshiyama Y, M Higuchi, B Zhang, SM Huang, N Iwata, TC Saido, et. al. (2007). Synapse loss and microglial activation precede tangles in a P301S tau-pathy mouse model. Neuron 53:337–351.
13. Bacskai BJ, ST Kajdasz, RH Christie, C Carter, D Games, P Seubert, et. al. (2001). Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy. Nat Med  7:369–372.
14. Nie, Q., Du, Xg. & Geng, My. (2011) Small molecule inhibitors of amyloid β peptide aggregation as a potential therapeutic strategy for Alzheimer's disease. Acta Pharmacol Sin 32, 545–551. https://doi.org/10.1038/aps.2011.1.
15. Chow VW, Mattson MP, Wong PC, Gleichmann M. (2010) An overview of APP processing enzymes and products. Neuromolecular Med. 12(1):1-12. doi:10.1007/s12017-009-8104-z.
16. De Strooper B, Vassar R, Golde T. (2010) The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol. 6(2):99-107. doi:10.1038/nrneurol.2009.218.
17. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, et al. (1999) Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286: 735–41.
18. Vassar R, Citron M. (2020) Abeta-generating enzymes: recent advances in beta- and gamma-secretase research. Neuron 27: 419–22.
19. Gao Y, Pimplikar SW. (2001) The gamma-secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus. Proc Natl Acad Sci U S A 98: 14979–84.
20. Kitazume S, Tachida Y, Oka R, Shirotani K, Saido TC, Hashimoto Y. (2001) Alzheimer's beta-secretase, beta-site amyloid precursor protein-cleaving enzyme, is responsible for cleavage secretion of a Golgi-resident sialyltransferase. Proc Natl Acad Sci U S A 98: 13554–9.
21. Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, et al. (2001) Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci. 4: 231–2.
22. Yang LB, Lindholm K, Yan R, Citron M, Xia W, Yang XL, et al. (2003) Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med. 9: 3–4.
23. Boutajangout A, Sigurdsson EM, Krishnamurthy PK. (2011) Tau as a therapeutic target for Alzheimer's disease. Curr Alzheimer Res. 8(6):666-677. doi:10.2174/156720511796717195.
24. Jadhav S, Avila J, Schöll M, Kovacs GG, Kövari E, Skrabana R, et al. (2019) A walk through tau therapeutic strategies. Acta Neuropathol Commun. 7(1):22. doi:10.1186/s40478-019-0664-z.
25. Hardy J, Selkoe DJ. (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 297: 353–6.
26. Bu G. (2009) Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci. 10: 333–44.
27. Ballatore C, Lee VMY, Trojanowski JQ. (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci. 8: 663–72.
28. Salminen A, Ojala J, Kauppinen A, et al. (2009) Inflammation in Alzheimer’s disease: amyloid-β oligomers trigger innate immunity defence via pattern recognition receptors. Prog Neurobiol. 87: 181–94.
29. Iwata N, Higuchi M, Saido TC. (2005) Metabolism of amyloid-β peptide and Alzheimer’s disease. Pharmacol Ther. 108: 129–48.
30. Saido TC, Iwata N. (2006) Metabolism of amyloid-β peptide and pathogenesis of Alzheimer’s disease: towards pre-symptomatic diagnosis, prevention and therapy. Neurosci Res. 254: 235–53.
31. Hussain R, Zubair H, Pursell S, Shahab M. (2018) Neurodegenerative Diseases: Regenerative Mechanisms and Novel Therapeutic Approaches. Brain Sci. 8(9):177. doi:10.3390/brainsci8090177.
32. Cai J, Hua F, Yuan L, Wei Tang, Jun Lu,  Shuchun Yu, et al. (2014) Potential therapeutic effects of neurotrophins for acute and chronic neurological diseases. Biomed Res Int. 2014:601084. doi:10.1155/2014/601084.
33. Miranda M, Morici JF, Zanoni MB, Bekinschtein P. (2019) Brain-Derived Neurotrophic Factor: A Key Molecule for Memory in the Healthy and the Pathological Brain. Front Cell Neurosci. 13:363. doi:10.3389/fncel.2019.00363.
34. Björklund A, Lindvall O. (2017) Replacing Dopamine Neurons in Parkinson's Disease: How did it happen? J Parkinsons Dis. 7(s1):S21-S31. doi:10.3233/JPD-179002.
35. Gaillard A, Jaber J. (2011) Rewiring the Brain with cell transplantation in Parkinson’s Disease. Trends in Neurosciences. 34 (23): 124-133.
36. Kirkeby A, Grealish S, Wolf DA, Nelander J, Wood J, Lundblad M, et. al. 2012) Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions. Cell Rep. 1(6):703–714.
37. Yang F, Liu Y, Tu J, Wan J, Zhang J, Wu B, et. al. (2014) Activated astrocytes enhance the dopaminergic differentiation of stem cells and promote brain repair through bFGF.  Nat Commun. 5:5627.  doi:10.1038/ncomms6627
38. Chakraborty A, Diwan A. (2022) Similarities Among Alzheimer’s Disease, Parkinson’s Disease and Dementia may Call for a Similar Treatment. AIMS-Medical Science. (In Press).
39. Donaghy PC, McKeith IG. (2014) The clinical characteristics of dementia with Lewy bodies and a consideration of prodromal diagnosis. Alz Res Therapy 6, 46 https://doi.org/10.1186/alzrt274.
40. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall, VS, et. al. (1998). Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147.
41. Rippon HJ and Bishop AE. (2004). Embryonic stem cells. Cell Prolif 37:23–34.
42. Wobus AM and Boheler KR. (2005). Embryonic stem cells: prospects for developmental biology and cell therapy. Physiol Rev 85:635–678.
43. Lennington JB, Yang Z, and Conover JC. (2003). Neural stem cells and the regulation of adult neurogenesis. Reprod Biol Endocrinol 1:99.
44. Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T and Gould. E (2001). Neurogenesis in the adult is involved in the formation of trace memories. Nature 410:372–376.
45. Shruster A, Melamed E, and Offen D. (2010). Neurogenesis in the aged and neurodegenerative brain. Apoptosis 15:1415– 1421.
46. Kim SU. (2004). Human neural stem cells genetically modified for brain repair in neurological disorders. Neuropathology 24:159–171.
47. Yasuhara T, Matsukawa N, Hara K, Yu G, Xu L, Maki M, et. al. (2006). Transplantation of human neural stem cells exerts neuroprotection in a rat model of Parkinson’s disease. J Neurosci 26:12497–12511.
48. Borlongan CV. (2012). Recent preclinical evidence advancing cell therapy for Alzheimer’s disease. Exp Neurol. 237:142– 146.
49. Qu T, Brannen L, Kim HM and Sugaya K. (2001). Human neural stem cells improve cognitive function of aged brain. Neuroreport 12:1127–1132.
50. Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello NA, Muller FJ, Loring, JF, et. al. (2009). Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci U S A 106:13594–13599.
51. Chakraborty A, Diwan A. (2021) Coculturing NSCs with Melanocyte Increased its Dopamine and Neural Factor Secretion. Acta Scientific Neurology (ISSN: 2582-1121), 4(5), 70-78.
52. Weiss JH, Yin HZ, and Choi DW. (1994). Basal forebrain cholinergic neurons are selectively vulnerable to AMPA/ kainate receptor-mediated neurotoxicity. Neuroscience 60: 659–664.
53. Kar S and Quirion R. (2004). Amyloid beta peptides and central cholinergic neurons: functional interrelationship and relevance to Alzheimer’s disease pathology. Prog Brain Res 145:261–274.
54. Tarasenko YI, Yu Y, Jordan PM, Bottenstein J and Wu P. (2004). Effect of growth factors on proliferation and phenotypic differentiation of human fetal neural stem cells. J Neurosci Res 78:625–636.
55. Doering LC and Snyder EY. (2000). Cholinergic expression by a neural stem cell line grafted to the adult medial septum/ diagonal band complex. J Neurosci Res. 61:597–604.
56. Arnhold S, Absenger Y, Klein H, Addicks K and Schraermeyer U. (2007). Transplantation of bone marrowderived mesenchymal stem cells rescue photoreceptor cells in the dystrophic retina of the rhodopsin knockout mouse. Graefes Arch Clin Exp Ophthalmol. 245:414–422.
57. Sanchez-Ramos J, Song S, Cardozo-Pelaez F, Hazzi C, Stedeford T, Willing A, et al. (2000). Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 164:247–256.
58. Lo Surdo J and Bauer SR. (2012). Quantitative approaches to detect donor and passage differences in adipogenic potential and clonogenicity in human bone marrow-derived mesenchymal stem cells. Tissue Eng Part C Methods 18:877–89.
59. Sadan O, Melamed E and Offen D. (2009). Bone marrow-derived mesenchymal stem cell therapy for neurodegenerative diseases. Expert Opin Biol Ther. 9:1487–1497.
60. Lee JK, Jin HK, and Bae JS. (2009). Bone marrow-derived mesenchymal stem cells reduce brain amyloid-beta deposition and accelerate the activation of microglia in an acutely induced Alzheimer’s disease mouse model. Neurosci Lett. 450:136–141.
61. Lee HJ, Lee JK, Lee H, Shin JW, Carter JE, Sakamoto T, et. al. (2010). The therapeutic potential of human umbilical cord blood-derived mesenchymal stem cells in Alzheimer’s disease. Neurosci Lett. 481:30–35.
62. Lee JK, Schuchman EH, Jin HK and Bae JS. (2012). Soluble CCL5 derived from bone marrow-derived mesenchymal stem cells and activated by amyloid beta ameliorates Alzheimer’s disease in mice by recruiting bone marrowinduced microglia immune responses. Stem Cells. 30:1544–1555.
63. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et. al.. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872.
64. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920.
65. Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C, et al. (2012). Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482:216–220.
66. Griffin WS, Sheng JG, Royston MC, Gentleman SM, McKenzie JE, Graham DJ, et. al. (1998). Glial-neuronal interactions in Alzheimer’s disease: the potential role of a ‘cytokine cycle’ in disease progression. Brain Pathol. 8:65–72.
67. Haga S, Akai K, and Ishii T. (1989). Demonstration of microglial cells in and around senile (neuritic) plaques in the Alzheimer brain. An immunohistochemical study using a novel monoclonal antibody. Acta Neuropathol. 77:569–575.
68. Pihlaja R, Koistinaho J, Malm T, Sikkila H, Vainio S and Koistinaho M. (2008). Transplanted astrocytes internalize deposited beta-amyloid peptides in a transgenic mouse model of Alzheimer’s disease. Glia 56:154–163.
69. Ian PM and Liang Tang Y. (2008). Genetic modification of stem cells for transplantation. Adv Drug Deliv Rev 60.2: 160–172.
70. Lindvall O and Kokaia Z. (2006). Stem cells in human neurodegenerative disorders—time for clinical translation? J Clin Invest 120:29–40.
71. Fisher LJ, Raymon HK, and Gage FH. (1993). Cells engineered to produce acetylcholine: therapeutic potential for Alzheimer’s disease. Ann N Y Acad Sci 695:278–284.
72. Habisch HJ, Schmid B, von Arnim CA, Ludolph AC, Brenner R and Storch A. (2009). Efficient processing of Alzheimer’s disease amyloid-beta peptides by neuroectodermally converted mesenchymal stem cells. Stem Cells Dev 19:629–633.
73. Hemming ML, Patterson M, Reske-Nielsen C, Lin L, Isacson O and Selkoe DJ. (2007). Reducing amyloid plaque burden via ex vivo gene delivery of an Aβ -degrading protease: a novel therapeutic approach to Alzheimer disease. PLoS Med. 4:e262.
74. Wu S, Sasaki A, Yoshimoto R, Kawahara Y, Manabe T, Kataoka K, et. al. (2008). Neural stem cells improve learning and memory in rats with Alzheimer’s disease. Pathobiology 75:186–194.
75. Tuszynski MH, Thal L, Pay M, Salmon DP, Sang HU, Bakay R, et al. (2005). A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med. 11:551–555.
76. Liu XY, Yang LP, Zhao L. (2020). Stem cell therapy for Alzheimer's disease. World J Stem Cells. 12(8):787-802. doi:10.4252/wjsc.v12.i8.787.
77. Alderson RF, Alterman AL, Barde YA and Lindsay RM. (1990). Brain-derived neurotrophic factor increases survival and differentiated functions of rat septal cholinergic neurons in culture. Neuron 5:297–306.
78. Li Y, Holtzman DM, Kromer LF, Kaplan DR, Chua-Couzens J, Clary DO, et. al. (1995). Regulation of TrkA and ChAT expression in developing rat basal forebrain: evidence that both exogenous and endogenous NGF regulate differentiation of cholinergic neurons. J Neurosci 15:2888–2905.
79. Nagahara AH and Tuszynski MH. (2011). Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov 10:209–219.
80. Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, GM Shaked GM, et al. (2009). Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat Med 15:331–337.
81. Xuan AG, Long DH, Gu HG, Yang DD, Hong LP and Leng SL. (2008). BDNF improves the effects of neural stem cells on the rat model of Alzheimer’s disease with unilateral lesion of fimbria-fornix. Neurosci Lett 440: 331–335.
82. Chakraborty A and A Diwan A. (2021) Modified neural stem cells: A new regimen for cell therapy of Alzheimer’s and Parkinson’s disease. Current Trends in Neurology 15, 43-48.
83. Chakraborty A, Diwan A. (2020) Cell-Cell interaction: A method to upgrade the Neural Cells Function. Journal of Neurology & Neurophysiology. 11(4): 001-003.
84. Chakraborty A, Diwan A. (2021) Coculturing NSCs with Melanocyte Increased its Dopamine and Neural Factor Secretion. Acta Scientific Neurology (ISSN: 2582-1121), 4(5), 70-78.
85. Chakraborty A, Diwan A. (2020) Alzheimer and it’s possible Therapy: A Review. Journal of Experimental Neurology. 1(4): 115-122.
86. Chakraborty A, Diwan A. (2019) Selection of Cells for Parkinson’s Disease Cell-Therapy. Int J Stem Cell Res Ther. 6:063. doi.org/10.23937/2469-570X/1410063.
87. Chakraborty A, Diwan A. (2021) Dementia in Parkinson’s Disease: It’s Therapeutics. Innovative Journal of Neurology and Neuroscience. 1(1): 1-4. Doi: IJNN.MS.ID.000501.
88. Björklund A, Dunnett SB, Brundin P, Stoessl AJ, Freed CR, Breeze RE, et. al. (2003) Neural transplantation for the treatment of Parkinson’s disease. THE LANCET Neurology Vol 2 July http://neurology.thelancet.com 437.
89. Rutkowski S, Mu L, Si T, Gai M, Sun M, Frueh J, He Q. (2019) Magnetically-propelled hydrogel particle motors produced by ultrasound assisted hydrodynamic electrospray ionization jetting, Colloids Surfaces B. Biointerfaces. 175; 44–55. https://doi.org/10.1016/j.colsurfb.2018.11.068.
90. Hu N, Zhang B, Gai M, Zheng C, Frueh J, He Q. (2017) Forecastable and Guidable Bubble-Propelled Microplate Motors for Cell Transport, Macromol. Rapid Commun. 38, 1600795. https://doi.org/10.1002/marc.201600795.