NEW INSIGHTS IN ALZHEIMER’S DISEASE: THE USE OF STEM CELLS

P. Galasso^1*, P. Felaco² and M.M. Corsi-Romanelli^3,4

¹ Aesthetic Medicine and Oral Medicine, “Gabriele d’Annunzio” University of Chieti-Pescara, Chieti, Italy;
² UOC Nephrology and Dialysis, Teramo Hospital, Teramo, Italy;
³ Department of Biomedical Sciences for Health, University of Milan, 20133 Milan, Italy;
⁴ Department of Experimental and Clinical Pathology, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy.

*Correspondence to:
Piero Galasso, MD,
Aesthetic Medicine and Oral Medicine,
“Gabriele d’Annunzio” University of Chieti-Pescara,
Chieti, Italy.
e-mail: pierogalassomail@gmail.com

ABSTRACT

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects the central nervous system (CNS), causing deterioration of neurons and gradual loss of memory, cognition, and language. AD is caused not only by abnormal protein amyloid-beta (Aβ), but also by tau protein and brain inflammation, which plays a key role in cognitive decline. Microglia of the innate immune system contribute to disease progression. Early diagnosis, unhealthy lifestyle, and poor metabolism and vascular health can influence the risk of developing the disease. Treating AD with new humanised monoclonal antibodies reduces Aβ plaques in the brain and modestly slows cognitive decline, especially in the initial phase of treatment, but it is not a definitive cure. Furthermore, the procedure can cause side effects such as edema and/or cerebral microhaemorrhages. Early treatment of AD has been shown to improve the therapeutic effect.

KEYWORDS: Alzheimer’s disease, neurodegenerative disorder, pathology, therapy, stem cell

INTRODUCTION

Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder that causes dementia and cognitive impairment (1). To date, much research has been conducted on AD, but no one has yet been able to understand what really drives the disease. However, with targeted therapeutic interventions, AD can now be partially controlled (2).

AD is characterized by protein alterations, synaptic dysfunction, neuroinflammation, and neuronal death (3).  The pathogenesis is still not fully understood, yet ongoing clinical trials are creating new therapeutic hope (4).  Research has been searching for effective treatments for AD since many years. Recently, the U.S. Food and Drug Administration (FDA) has approved several drugs for the treatment of this disease, which are aimed not only at alleviating symptoms but also to address AD biologically (5).  This has allowed significant progress to be made in tackling the disease, but much work remains to be done.

Pathological studies conducted on the brains of deceased AD patients have shown the formation of aggregates and plaques of amyloid-beta (Aβ) proteins in the spaces between neurons (6). Neurofibrillary tangles (NFTs) of tau proteins also accumulate in nerve cells (7). Studies report that Aβ accumulates early and NFTs form when nerve cell damage is ongoing, but symptoms have not yet appeared (8).  These altered proteins lead to neurodegeneration because they no longer allow cross-talk between nerve cells.

DISCUSSION

In the physiological pathway, amyloid precursor protein (APP) is normally cleaved by enzymes such as α-secretase, resulting in the failure of Aβ production (9).  In the pathological pathway, Aβ produces peptides such as Aβ40 and the aggregating Aβ42. Aβ42 can form soluble oligomers that are highly toxic to synapses that aggregate into lakes, reducing extracellular fluid (10) Synaptic toxicity results in a reduction of NMDA and AMPA receptors, impaired long-term potentiation, and an increase in intracellular Ca²⁺ (11).  These reactions lead to microglia activation, the production of pro-inflammatory cytokines, and neuroinflammation (12).

Tau protein destabilizes microtubules in neurons, and hyperphosphorylation of Tau involves the kinases GSK3β and CDK5 (13,14).   This protein loses affinity for microtubules and forms intracellular NFTs (15). Cellular effects include microtubule instability, impaired axonal transport, mitochondrial dysfunction, and apoptotic cell death (16). Tau pathology includes neuroinflammation involving microglia and astrocytes (17).

Aβ activates Toll-like receptors (TLRs) and TREM2 of microglia, with the production of pro-inflammatory cytokines, such as IL-1β and tumor necrosis factor (TNF), and reactive oxygen species (ROS) (18).  This creates a chronic inflammatory state with progressive neuronal damage, mitochondrial dysfunction, and oxidative stress with reduced ATP production, increased ROS, and damage to membrane lipids, mitochondrial DNA, and synaptic proteins (19). Cerebral damage may present with rapidly occurring synaptic changes, loss of dendritic spines, reduction of excitatory synapses, alterations in glutamate metabolism, cholinergic deficit with degeneration of basal nucleus neurons, cognitive decline due to synaptic loss, and subsequent neuronal death (20).

In order to understand disease risk, DNA studies of genetic variants have indicated that immune and inflammatory processes may play a significant role in this disease (21). However, poor diet, smoking, diabetes, physical inactivity, and vascular disease have also been found to be risk factors (22). Genetic factors that increase the production of Aβ42 may involve mutations in APP, PSEN1, and PSEN2 (23).  The most common sporadic form and primary genetic risk factor is the APOE ε4 allele, which reduces Aβ clearance, increases inflammation, and promotes Aβ deposition (24). Cortico-hippocampal neurodegeneration with cognitive symptoms is linked to Tau protein, which primarily affects the hippocampus, entorhinal cortex, and temporoparietal cortex (25).

New drugs such as donanemab, aducanumab and lecanemab aim to bind to Aβ proteins and then eliminate them, resulting in improved cognitive function (26). Current research into AD treatment has produced drugs that improve the disease, including dementia, but do not alter the course of neurodegeneration, although reducing Aβ slows the process. In recent years, monoclonal antibodies targeting Aβ, such as donanemab, aducanumab, and lecanemab, have been approved by FDA (2). The humanised monoclonal antibody aducanumab binds with high affinity to the neurotoxic soluble protofibrils of Aβ. After a year and a half of treatment, improvement in patients’ clinical decline has been observed compared to untreated patients. Additionally, donanemab, an antibody that targets the deposited altered Aβ protein, resulted in improved cognitive performance after approximately 6 months of treatment, although further studies are needed to confirm these results (27). The accumulation of Aβ and tau proteins in AD is nonspecific, as these proteins can also accumulate in other diseases affecting the central nervous system (CNS) (5).

AD Patients also have accumulations of other proteins in the brain, such as α-synuclein, which can appear before Aβ plaques and cause vascular damage (28).  Since other factors, for example, vascular and immune factors, contribute to the development of the disease, Aβ-reducing treatments are only part of the therapy (29). There is often a gap of decades between the accumulation of Aβ and cognitive decline (30). Recent studies have shown that many elderly individuals (>75 years old) who tested positive for Aβ on spinal fluid tests performed with positron emission tomography (PET) or computed tomography (CT) scans remained cognitively healthy (31). This may indicate that Aβ is not the sole cause of AD (32).

Stem cells are highly plastic cells capable of transforming into various specialized cell types. They may differentiate into new neurons and replace damaged or dead neurons in AD (33). Stem cells can also intervene in inflammatory processes, reducing their severity and promoting synapses (34,35). The cell types used are mesenchymal stem cells from bone marrow or adipose tissue, and adult induced pluripotent stem cells reprogrammed to behave like embryonic stem cells. The use of these cells in AD has shown improvements in memory and a reduction in Aβ plaques (35,36) (Fig.1). In animal models, injection using embryonic stem cells from cell cultures has been seen to replace damaged neurons in Alzheimer’s disease (AD), favoring synapses, improving memory, and reducing cerebral inflammation (37).

Fig. 1. Cell cultures of embryonal stem cells injected in damaged brain tissue produce new neurons and lead to improvement of the disease and also reduce neurodegeneration and inflammation.

CONCLUSIONS

Recent studies on AD are shedding light on this complex neurodegenerative disorder. Today, attention has shifted beyond the focus on Aβ and NFTs, and new research reveals a much more complex picture involving the immune and inflammatory systems, vascular and metabolic abnormalities, and genetic factors. Diagnostic methods, advanced neuroimaging techniques, and early diagnosis have proven to be strategies that are opening up innovative new avenues that can reduce protein metabolism and regulate the immune system. The knowledge gained to date about this disease has proven insufficient, and therefore, many molecular and clinical challenges remain to be addressed in AD.

Conflict of interest

The authors declare that they have no conflict of interest.

REFERENCES

1. Querfurth HW, LaFerla FM. Alzheimer’s Disease. New England Journal of Medicine. 2010;362(4):329-344. doi:https://doi.org/10.1056/nejmra0909142
2. Mintun MA, Lo AC, Duggan Evans C, et al. Donanemab in Early Alzheimer’s Disease. New England Journal of Medicine. 2021;384(18). doi:https://doi.org/10.1056/nejmoa2100708
3. Verma A, Shteinfer-Kuzmine A, Kamenetsky N, et al. Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer’s disease protects against mitochondrial dysfunction and mitigates brain pathology. Translational Neurodegeneration. 2022;11:58. doi:https://doi.org/10.1186/s40035-022-00329-7
4. Bhardwaj S. CRISPR/Cas9 gene editing: New hope for Alzheimer’s disease therapeutics. Journal of Advanced Research. 2021;40:207-221. doi:https://doi.org/10.1016/j.jare.2021.07.001
5. Varadharajan A, Davis AM, Ghosh A, et al. Guidelines for pharmacotherapy in Alzheimer’s disease – A primer on FDA-approved drugs. Journal of Neurosciences in Rural Practice. 2023;14(4):566-573. doi:https://doi.org/10.25259/jnrp_356_2023
6. Oakley H, Cole SL, Logan S, et al. Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer’s Disease Mutations: Potential Factors in Amyloid Plaque Formation. The Journal of Neuroscience. 2006;26(40):10129-10140. doi:https://doi.org/10.1523/JNEUROSCI.1202-06.2006
7. Bloom GS. Amyloid-β and tau: the Trigger and Bullet in Alzheimer Disease Pathogenesis. JAMA neurology. 2014;71(4):505-508. doi:https://doi.org/10.1001/jamaneurol.2013.5847
8. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer’s disease. The Lancet. 2011;377(9770):1019-1031. doi:https://doi.org/10.1016/s0140-6736(10)61349-9
9. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO molecular medicine. 2016;8(6):595-608. doi:https://doi.org/10.15252/emmm.201606210
10. Günaydin C, Sondhi D, Kaminsky SM, et al. AAVrh.10 Delivery of Novel APOE2-Christchurch Variant Suppresses Amyloid and Tau Pathology in Alzheimer’s Disease Mice. Molecular Therapy. 2024;32(12):4303-4318. doi:https://doi.org/10.1016/j.ymthe.2024.11.003
11. Grabauskas G, Chapman H, Wheal HV. Role of protein kinase C in modulation of excitability of CA1 pyramidal neurons in the rat. Neuroscience. 2006;139(4):1301-1313. doi:https://doi.org/10.1016/j.neuroscience.2006.01.014
12. Thakur S, Dhapola R, Sarma P, Medhi B, Reddy DH. Neuroinflammation in Alzheimer’s Disease: Current Progress in Molecular Signaling and Therapeutics. Inflammation. 2022;46(1). doi:https://doi.org/10.1007/s10753-022-01721-1
13. Man VH, He X, Gao J, Wang J. Phosphorylation of Tau R2 Repeat Destabilizes Its Binding to Microtubules: A Molecular Dynamics Simulation Study. ACS chemical neuroscience. 2023;14(3):458-467. doi:https://doi.org/10.1021/acschemneuro.2c00611
14. Baltissen D, Bold CS, Rehra L, et al. APPsα rescues CDK5 and GSK3β dysregulation and restores normal spine density in Tau transgenic mice. Frontiers in Cellular Neuroscience. 2023;17. doi:https://doi.org/10.3389/fncel.2023.1106176
15. Yoshiyama Y, Higuchi M, Zhang B, et al. Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model. Neuron. 2007;53(3):337-351. doi:https://doi.org/10.1016/j.neuron.2007.01.010
16. Ahn EH, Park JB. Molecular Mechanisms of Alzheimer’s Disease Induced by Amyloid-β and Tau Phosphorylation Along with RhoA Activity: Perspective of RhoA/Rho-Associated Protein Kinase Inhibitors for Neuronal Therapy. Cells. 2025;14(2):89-89. doi:https://doi.org/10.3390/cells14020089
17. Chen Y, Yu Y. Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation. Journal of Neuroinflammation. 2023;20(1). doi:https://doi.org/10.1186/s12974-023-02853-3
18. Boza-Serrano A, Ruiz R, Sanchez-Varo R, et al. Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease. Acta Neuropathologica. 2019;138(2):251-273. doi:https://doi.org/10.1007/s00401-019-02013-z
19. Begni B, Brighina L, Sirtori E, et al. Oxidative stress impairs glutamate uptake in fibroblasts from patients with alzheimer’s disease. Free Radical Biology and Medicine. 2004;37(6):892-901. doi:https://doi.org/10.1016/j.freeradbiomed.2004.05.028
20. Martín-Belmonte A, Aguado C, Rocío Alfaro-Ruíz, et al. Age-Dependent Shift of AMPA Receptors From Synapses to Intracellular Compartments in Alzheimer’s Disease: Immunocytochemical Analysis of the CA1 Hippocampal Region in APP/PS1 Transgenic Mouse Model. Frontiers in aging neuroscience. 2020;12. doi:https://doi.org/10.3389/fnagi.2020.577996
21. Guerreiro R, Wojtas A, Bras J, et al. TREM2 Variants in Alzheimer’s Disease. New England Journal of Medicine. 2013;368(2):117-127. doi:https://doi.org/10.1056/nejmoa1211851
22. Rochoy M, Rivas V, Chazard E, et al. Factors Associated with Alzheimer’s Disease: An Overview of Reviews. The Journal of Prevention of Alzheimer’s Disease. 2019;6(2):121-134. doi:https://doi.org/10.14283/jpad.2019.7
23. Lin YT, Seo J, Gao F, et al. APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types. Neuron. 2018;98(6):1141-1154.e7. doi:https://doi.org/10.1016/j.neuron.2018.05.008
24. Insel PS, Hansson O, Mattsson-Carlgren N. Association Between Apolipoprotein E ε2 vs ε4, Age, and β-Amyloid in Adults Without Cognitive Impairment. JAMA Neurology. 2021;78(2):229. doi:https://doi.org/10.1001/jamaneurol.2020.3780
25. Vilella A, Bodria M, Papotti B, et al. PCSK9 ablation attenuates Aβ pathology, neuroinflammation and cognitive dysfunctions in 5XFAD mice. Brain, behavior, and immunity. 2024;115:517-534. doi:https://doi.org/10.1016/j.bbi.2023.11.008
26. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer’s Disease. New England Journal of Medicine. 2022;388(1):9-21. doi:https://doi.org/10.1056/nejmoa2212948
27. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330(6). doi:https://doi.org/10.1001/jama.2023.13239
28. Wang J, Zheng B, Yang S, Hu M, Wang JH. Differential Circulating Levels of Naturally Occurring Antibody to α-Synuclein in Parkinson’s Disease Dementia, Alzheimer’s Disease, and Vascular Dementia. Frontiers in Aging Neuroscience. 2020;12. doi:https://doi.org/10.3389/fnagi.2020.571437
29. Yang AC, Vest RT, Kern F, et al. A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk. Nature. 2022;603(7903):885-892. doi:https://doi.org/10.1038/s41586-021-04369-3
30. Huber CM, Yee C, May T, Dhanala A, Mitchell CS. Cognitive Decline in Preclinical Alzheimer’s Disease: Amyloid-Beta versus Tauopathy. Journal of Alzheimer’s Disease. 2017;61(1):265-281. doi:https://doi.org/10.3233/jad-170490
31. Bergeret S, Queneau M, Rodallec M, et al. [¹⁸F]FDG PET may differentiate cerebral amyloid angiopathy from Alzheimer’s disease. European Journal of Neurology. 2021;28(5):1511-1519. doi:https://doi.org/10.1111/ene.14743
32. Moro ML, Phillips AN, Gaimster K, et al. Pyroglutamate and Isoaspartate modified Amyloid-Beta in ageing and Alzheimer’s disease. Acta neuropathologica communications. 2018;6(1). doi:https://doi.org/10.1186/s40478-017-0505-x
33. Si Z, Wang X. Stem cells Therapies in Alzheimer’s disease: applications for disease modeling. Journal of Pharmacology and Experimental Therapeutics. 2021;377(2):JPET-MR-2020-000324. doi:https://doi.org/10.1124/jpet.120.000324
34. Corey S, Bonsack B, Heyck M, et al. Harnessing the anti-inflammatory properties of stem cells for transplant therapy in hemorrhagic stroke. Brain Hemorrhages. 2020;1(1):24-33. doi:https://doi.org/10.1016/j.hest.2019.12.005
35. Chang J, Li YY, Shan X, et al. Neural stem cells promote neuroplasticity: a promising therapeutic strategy for the treatment of Alzheimer’s disease. Neural Regeneration Research. 2023;19(3):619-628. doi:https://doi.org/10.4103/1673-5374.380874
36. Zhang J, Zhang Y, Wang J, Xia Y, Zhang J, Chen L. Recent Advances in Alzheimer’s disease: Mechanisms, Clinical Trials and New Drug Development Strategies. Signal Transduction and Targeted Therapy. 2024;9(1). doi:https://doi.org/10.1038/s41392-024-01911-3
37. Bhatti JS, Khullar N, Mishra J, et al. Stem cells in the treatment of Alzheimer’s disease – Promises and pitfalls. Biochimica Et Biophysica Acta: Molecular Basis Of Disease. 2023;1869(6):166712-166712. doi:https://doi.org/10.1016/j.bbadis.2023.166712