Alzheimer's Disease New Therapeutics: Pioneering Approaches to Tackle a Growing Concern

Alzheimer's disease (AD) is a complex neurological disorder that significantly impacts the aging population. Pathological changes begin to occur in the brains of patients before any clinical manifestations are observed, including the accumulation of amyloid-β (Aβ) toxins, the formation of neuroprotofibrillary tangles (NFTs) by hyperphosphorylated tau proteins, and the neurodegeneration resulting from the secretion of neurotoxins and inflammatory factors. Molecular biomarkers, including APP (Amyloid precursor protein), Tau, BACE1 (Beta-site APP-cleaving enzyme 1), ApoE (Apolipoprotein E), GLP1R (Glucagon-Like Peptide-1 Receptor), NGF (Nerve Growth Factor), BDNF (Brain-Derived Neurotrophic Factor), GSK3B (Glycogen Synthase Kinase 3 Beta), CASP9 (Caspase-9), CLU (Clusterin), AGER (Advanced Glycation End Product Receptor), DPYSL2 (Dihydropyrimidinase Like 2), and PNMT (phenylethanolamine-N-methyl-transferase), play crucial roles in its pathogenesis. Various investigations utilize these biomarkers, including neuroprotective effects, tau uptake, and impact on neurite growth, which have physiological functions but also contribute to pathological conditions when dysregulated(1-6).

The process from research to clinical success is challenging, marked by ongoing trials exploring novel Alzheimer's therapeutics targeting Aβ, tau, neuroinflammation, and synaptic preservation(1,3). Notably, FDA-approved anti-Aβ antibodies like aducanumab and lecanemab have emerged(7,8). The research landscape relies on recombinant proteins such as Aβ, tau, GLP1R, and ApoE to drive drug discovery and decipher target interactions(4,9–12). Sino Biological is at the forefront of Alzheimer's research, offering recombinant Alzheimer's biomarkers and providing valuable insights for disease diagnosis and novel therapeutics development.

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Physiological and Pathological Roles

A group of biomarkers plays pivotal roles in both physiological processes and pathological conditions. NGF is vital for the growth and maintenance of nerve cells, and its dysregulation is associated with neurodegenerative diseases like Alzheimer's(13). CASP9 is essential for programmed cell death (apoptosis) and tissue homeostasis, and its activation in AD brain may lead to NFT formation(14). CLU has diverse physiological roles, including lipid transport and cell differentiation, yet elevated levels are observed in neurodegenerative conditions such as AD15. AGER plays a role in normal tissue development but can trigger inflammation and oxidative stress in pathological situations(16). DPYSL2 is crucial for neuronal development but may also be involved in neurodegenerative disorders(17). PNMT is essential for stress-related hormone synthesis, while BDNF supports neuronal survival and plasticity(18). GSK3B regulates various cellular functions, but its dysregulation can lead to neurodegenerative and mood disorders(19,20). BACE1 is another biomarker implicated in the production of Aβ in AD, making it a target for therapeutic interventions in AD21. The GLP1R agonists have been shown to play roles in anti-neuroinflammatory, attenuating oxidative stress, and neurotrophic effects, making them potential drug candidates for the treatment of AD(12,22).

From Bench to Bedside

The transition from laboratory findings to clinical success requires rigorous investigation and validation. Amongst clinical trials that are evaluating novel AD therapeutics, efforts to reduce Aβ accumulation and aggregation have garnered significant attention. Anti-Aβ antibodies, such as aducanumab and lecanemab have received FDA approval in 2021 and 2023 respectively(7,8). ApoE, particularly the ApoE ε4 allele, is a well-established genetic risk factor for AD. Strategies targeting ApoE expression and lipid metabolism pathways could decrease Aβ deposition and enhance Aβ clearance(10). Other approaches include BACE inhibitors to reduce Aβ production and γ-secretase modulators to influence Aβ cleavage(21). Tau protein aggregation is another critical facet of AD pathology. Targeting tau kinases and stabilizing microtubules to prevent tau tangle formation are areas of active research(11). Preserving synaptic function and connectivity is critical in AD treatment. Neurotrophic factors, such as NGF and BDNF, are being explored to enhance neuronal survival and synaptic plasticity(13,18). Finally, GLP-1 receptor agonists, initially approved for type 2 diabetes and obesity, have been explored for the treatment of AD by reducing neuroinflammation(22).

Application in Research

To advance drug discovery and understand target interactions, access to high-quality reagents is essential. Recombinant proteins, such as Aβ peptides, tau protein, and ApoE variants, facilitate mechanistic studies and preclinical evaluations, aiding the development of innovative AD therapies. Gao et al investigated the interaction between GSK-3β and PKG using human GSK-3β protein (Cat#: 10044-H07B, Sino Biological), and found that the neuroprotective effects of icariside II were attributed to interference with PKG/GSK-3β/autophagy axis(20). Endicott et al. treated lysosomes with Tau protein (Cat#: 10058-H07E, Sino Biological) and protease inhibitors to study chaperone-mediated autophagy (CMA) substrate uptake in isolated lysosomes, and found enhanced Tau uptake and reduced GFAP phosphorylation in liver lysosomes from buparlisib or pictilisib-treated mice(23). Sperling et al investigated that binding of AChE to laminin-1 alters AChE activity and leads to increased neurite growth in culture. But only in about 0.5% of cells could detect cell-associated recombinant AChE (Cat#: 50543-M08H, Sino Biological), mostly to the cell body(6). Zhang et al. looked into the interaction assay of their graphene oxide (GO) nanoparticles with purified APP or BACE1 protein (Sino Biological) and found that GO treatment alleviates Aβ levels and improves memory in mice(24). Vojdani et al. utilized recombinant β-NGF and BDNF protein (Sino Biological) to investigate the immune reactivity of Anti-Aβ-42 peptide with tissue antigens that may be involved in neurodegenerative disorders, and found that the antibody was highly reactive with β-NGF and BDNF(25).

References

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7. van Dyck, C. H. et al. Lecanemab in Early Alzheimer’s Disease. New England Journal of Medicine 388, 9–21 (2023).

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14. Rohn, T. T., Rissman, R. A., Davis, M. C., Kim, Y. E., Cotman, C. W., & Head, E. Immunohistochemical analysis of caspase expression in the brains of individuals with obesity or overweight. Neurobiology of disease 11(2), 341-354 (2002).

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16. Bennet, A. M. et al. Genetic association of sequence variants near AGER/NOTCH4 and dementia. Journal of Alzheimer’s Disease 24, 475–484 (2011).

17. Noura, M. et al. Pivotal role of DPYSL2A in KLF4-mediated monocytic differentiation of acute myeloid leukemia cells. Sci Rep 10, (2020).

18. Henjum, K. et al. Cerebrospinal fluid catecholamines in Alzheimer’s disease patients with and without biological disease. Transl Psychiatry 12, (2022).

19. Lauretti, E., Dincer, O. & Praticò, D. Glycogen synthase kinase-3 signaling in Alzheimer’s disease. Biochimica et Biophysica Acta - Molecular Cell Research vol. 1867 Preprint at https://doi.org/10.1016/j.bbamcr.2020.118664 (2020).

20. Gao, J. et al. Icariside II, a phosphodiesterase 5 inhibitor, attenuates cerebral ischaemia/reperfusion injury by inhibiting glycogen synthase kinase-3β-mediated activation of autophagy. Br J Pharmacol 177, 1434–1452 (2020).

21. Hampel, H. et al. The β-Secretase BACE1 in Alzheimer’s Disease. Biological Psychiatry vol. 89 745–756 Preprint at https://doi.org/10.1016/j.biopsych.2020.02.001 (2021).

22. Du, H., Meng, X., Yao, Y., & Xu, J. The mechanism and efficacy of GLP-1 receptor agonists in the treatment of Alzheimer’s disease. Frontiers in Endocrinology 13, 1033479 (2022).

23. Endicott, S. J., Ziemba, Z. J., Beckmann, L. J., Boynton, D. N. & Miller, R. A. Inhibition of class I PI3K enhances chaperone-mediated autophagy. J Cell Biol 219, (2020).

24. Zhang, J. et al. Graphene oxide improves postoperative cognitive dysfunction by maximally alleviating amyloid beta burden in mice. Theranostics 10, 11908–11920 (2020).

25. Vojdani, A. & Vojdani, E. Amyloid-Beta 1-42 Cross-Reactive Antibody Prevalent in Human Sera May Contribute to Intraneuronal Deposition of A-Beta-P-42. Int J Alzheimers Dis 2018, (2018).