Posts Tagged ‘Acetylcholinesterase’

Overview of Alzheimer’s Disease and Novel Treatments Targeting Beta-Amyloid Deposits

Reporter: Sharada Kittur, Research Assistant 1, Synthetic Biology in Drug Discovery

Alzheimer’s disease (AD) is a common type of dementia. People diagnosed with this disease suffer memory loss. Severe forms of the condition prevent the patients from responding to the environment. Alzheimer’s disease patients may also experience difficulty completing basic tasks, decreased or poor judgement as their executive function competence declines. Frequent changes in mood, personality, or behavior. AD is the 7th leading cause of death in the United States, and the 5th leading cause of death for adults aged 65 and over. Unlike cancer and heart disease, whose death rates are declining, the number of people struggling with Alzheimer’s disease is projected to increase in the coming years.  

Currently, there are no cures for the disease. Many of the drugs on the market target only symptoms of the disease. The key mechanism of action (MOA) of AD drugs is inhibiting acetylcholinesterase. Acetylcholinesterase (AChE) is an enzyme that breaks down a neurotransmitter called acetylcholine (Ach), which is an important factor for memory functions. On average, Alzheimer’s disease patients have lower concentrations of acetylcholine. In order to treat this biomarker, scientists found molecules that can inhibit AChE, and reduce the breakdown of acetylcholine, thus improving the memory of patients with Alzheimer’s disease by enabling average levels of Ach. Some examples of AChE inhibitors currently on the market are

  • donepezil,
  • rivastigmine, and
  • galantamine. 

One of the main causes of Alzheimer’s disease is believed to be the buildup of beta-amyloid plaques in the brain. Beta-amyloid is a toxic protein that is normally produced in small amounts in the brain. Then microglia, a type of macrophages in the nervous system, clear out the beta-amyloid deposits. In patients with Alzheimer’s disease, the microglia can’t clear away the beta-amyloid, and this obstructs neural function and attacks neurons. The cause of the microglia’s malfunction is still unknown, but it could be due to a gene called TREM2, that tells the microglia to clear the beta-amyloid proteins. When TREM2 doesn’t function properly, the microglia collects all of the beta-amyloid, but isn’t able to dispose of it. It then releases inflammatory chemicals, which increase the production of the amyloid precursor protein (APP). This also increases the production of β-secretase and γ-secretase, enzymes that form beta-amyloid by breaking down APP. This further exacerbates the problem. 

On July 06, 2023, the Food and Drug Administration (FDA) fully approved Leqembi (lecanemab-irmb) to treat Alzheimer’s disease. Leqembi is a monoclonal antibody that specifically targets beta-amyloid proteins in the brain. It binds to the beta-amyloid proteins and clears them. This is very promising as in placebo-controlled clinical trials, it significantly decreased the beta-amyloid deposits in 18 months, and delayed cognitive decline by 5.3 months. It’s the first beta-amyloid targeting drug that was approved by the FDA as a Traditional Approval. 

Leqembi is not a cure, however. It significantly slows down the mental function deterioration of the patients, but hasn’t been shown to fully maintain it at the current level over time. In addition, Leqembi has many side effects, such as headaches, and presents amyloid-related imaging abnormalities (ARIAs). ARIAs can cause swelling and bleeding in parts of the brain, but they should be temporary for most patients. Severe ARIAs only occur in a very small percentage of patients. 

As researchers make progress in understanding the complex causes of Alzheimer’s disease, new treatments that are developed can help improve the lives of millions of people worldwide. 


“Alzheimer’s Association Welcomes U.S. FDA Traditional Approval of Leqembi: Full Details.” Alzheimer’s Disease and Dementia, Alzheimer’s Association, 6 July 2023, www.alz.org/news/2023/lecanemab-leqembi-traditional-fda-approval-full#:~:text=CHICAGO%2C%20July%206%2C%202023%20%E2%80%94,confirmation%20of%20elevated%20amyloid%20beta.

Smith, Tyler. “How Well Does Leqembi Work to Fight Alzheimer’s? First FDA-Approved Alzheimer’s Drug Offers Both Promise and Challenges.” UCHealth Today, 11 Aug. 2023, www.uchealth.org/today/how-well-does-leqembi-fight-alzheimers-first-fda-approved-alzheimers-drug/

Wang, Shaoxun, et al. “Is Beta-Amyloid Accumulation a Cause or Consequence of Alzheimer’s Disease?” Journal of Alzheimer’s Parkinsonism & Dementia, U.S. National Library of Medicine, 17 Nov. 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC5555607/

“What Happens to the Brain in Alzheimer’s Disease?” National Institute on Aging, U.S. Department of Health and Human Services, 16 May 2017, www.nia.nih.gov/health/what-happens-brain-alzheimers-disease#:~:text=In%20a%20person%20with%20Alzheimer’s,beta%2Damyloid%20and%20tau%20proteins.

“What Is Alzheimer’s Disease?” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 26 Oct. 2020, www.cdc.gov/aging/aginginfo/alzheimers.htm#:~:text=Alzheimer’s%20disease%20is%20the%20most,thought%2C%20memory%2C%20and%20language.


Other related articles published in this Open Access Online Scientific Journal include the following:

Alzheimer’s Disease: Novel Therapeutical Approaches — Articles of Note @PharmaceuticalIntelligence.com

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


Role of infectious agent in Alzheimer’s Disease?

Alzheimer’s disease, snake venome, amyloid and transthyretin

Alzheimer’s Disease – tau art thou, or amyloid

Breakthrough Prize for Alzheimer’s Disease 2016

Tau and IGF1 in Alzheimer’s Disease

Amyloid and Alzheimer’s Disease

Important Lead in Alzheimer’s Disease Model

BWH Researchers: Genetic Variations can Influence Immune Cell Function: Risk Factors for Alzheimer’s Disease,DM, and MS later in life

BACE1 Inhibition role played in the underlying Pathology of Alzheimer’s Disease

Late Onset of Alzheimer’s Disease and One-carbon Metabolism

Alzheimer’s Disease Conundrum – Are We Near the End of the Puzzle?

Ustekinumab New Drug Therapy for Cognitive Decline resulting from Neuroinflammatory Cytokine Signaling and Alzheimer’s Disease

New Alzheimer’s Protein – AICD

Developer of Alzheimer’s drug Exelon at Hebrew University’s School of Pharmacy: Israel Prize in Medicine awarded to Prof. Marta Weinstock-Rosin

TyrNovo’s Novel and Unique Compound, named NT219, selectively Inhibits the process of Aging and Neurodegenerative Diseases, without affecting Lifespan

@NIH – Discovery of Causal Gene Mutation Responsible for two Dissimilar Neurological diseases: Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD)

Introduction to Nanotechnology and Alzheimer disease

Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious Depression

New ADNI Project to Perform Whole-genome Sequencing of Alzheimer’s Patients,

Brain Biobank

Removing Alzheimer plaques

Tracking protein expression

Schizophrenia genomics

Breakup of amyloid plaques

Mindful Discoveries

Beyond tau and amyloid

Serum Folate and Homocysteine, Mood Disorders, and Aging

Long Term Memory and Prions

Retromer in neurological disorders

Neurovascular pathways to neurodegeneration

Studying Alzheimer’s biomarkers in Down syndrome

Amyloid-Targeting Immunotherapy Targeting Neuropathologies with GSK33 Inhibitor

Brain Science

Sleep quality, amyloid and cognitive decline

microglia and brain maintenance

Notable Papers in Neurosciences

New Molecules to reduce Alzheimer’s and Dementia risk in Diabetic patients

The Alzheimer Scene around the Web

MRI Cortical Thickness Biomarker Predicts AD-like CSF and Cognitive Decline in Normal Adults



  • Alzheimer’s disease
  • microglia
  • gliosis
  • neurodegeneration
  • inflammation


Read Full Post »

Melatonin and its effect on acetylcholinesterase activity in erythrocytes

Author: S. Chakravarty, PhD


Objective: The study was conducted to see the effect of melatonin on the activity of acetylcholinesterase in red blood cells.

Mammalian red blood cells contain membrane-bound acetylcholinesterase which acts as biomarkers of oxidative imbalance. Melatonin is a powerful free radical scavenger and upregulates several antioxidant enzymes to reduce oxidative stress. Being an effective antioxidant, it may initiate variation in erythrocyte acetylcholinesterase activity.

The study was carried out on twenty-nine subjects of both sexes who gave their informed consent for the use of their blood samples for the study (Chakravarty and Rizvi, 2011a). The red cells isolated from blood collected at two different timings of the day, viz., 10:00 a.m. and 10:00 p.m.,were subjected to in vitro treatment with melatonin in a dose-dependant manner followed by the assay of enzyme activity (Ellman et al., 1961).

Acetylcholinesterase (AChE) is also found on the red blood cell membranes, where it constitutes the Yt blood group of antigen, which is a blood-group determining protein. AChE has the features of a secreted rather than a transmembrane protein because it lacks long hydrophobic stretches, other than that which forms the signal peptide (Li et al., 1991). Besides, acetylcholinesterase activity in erythrocytes may be considered as a marker of central cholinergic status (Kaizer et al., 2008). AChE shows highest activity in the immature rat brain is at 6.00 a.m. and lowest after midnight, which undergoes a reversal after attaining maturity (Moudgil and Kanungo, 1973). The enzyme also exhibits annual changes in its activity (Lewandowski, 2008). Acetylcholinesterase activity has been used to for studying the activity pattern of human erythrocytes (Prall et al., 1998). Free radicals and increased oxidative stress have been found to reduce AChE activity (Molochkina et al., 2005). This indicates that melatonin may have some relation with the circadian rhythmicity of acetylcholinesterase activity.

The concentration-dependant assay of AChE activity in red cells bear close relation with the circadian rhythm in humans thus sharing a similar conclusion with that mentioned by Moudgil and Kanungo (Moudgil and Kanungo, 1973). The effect of melatonin on enzyme functions in erythrocytes follows rhythmic modulation with day/night cycle. The samples obtained in the morning exhibit significantly higher activity of acetylcholinesterase than those obtained during the night-time. The samples collected at two different timings of the day show different response to in vitro melatonin treatment. The rise in AChE activity is more pronounced at low doses of melatonin. Our results indicate significant increase in acetylcholinesterase activity in diurnal as well as nocturnal blood samples at different concentrations of exogenous melatonin (Rizvi and Chakravarty, 2011). At supraphysiological doses, the enzyme activity exhibits no significant change, owing to the prooxidative influence exerted by melatonin (Marchiafava and Longoni, 1999).

Acetylcholinesterase activity is affected by the hydrophobic environment of the cell membrane and depends on the plasma membrane fluidity and surface charge of the cell (Klajnert et al., 2004).  The activity of AChE depends largely on the biophysical features of membrane. Oxidative stress decreases the fluidity of membrane lipid bilayer, thus affecting its normal functions (Goi et al., 2005).  Such are the ill-effects of oxidative radicals that tend to increase with aging. The decrease in AChE correlates significantly with age-induced oxidative stress (Jha and Rizvi, 2009).  On the basis of our study we conclude that melatonin modulates acetylcholinesterase activity in erythrocytes. The rhythmicity observed in the activity of acetylcholinesterase in response to the melatonin confirms our opinion on the relationship between the enzyme function, pineal secretion and pharmacological dosage of the indole antioxidant.


  1. Chakravarty S, Rizvi SI, Circadian modulation of sodium-potassium ATPase and sodium-proton exchanger in human erythrocytes: in vitro effect of melatonin. <a href=”80-6. “http://www.ncbi.nlm.nih.gov/pubmed/21366966
  2. Ellman GL, Courtney KD,      Andres Jr V, Featherstone RM, A new and rapid colorimeteric determination of acetylcholinesterase activity. Biochem Pharmacol 1961; 7(2): 88–95.
  3. Goi G, Cazzola R,      Tringali C, Massaccesi L, Volpe SR, Rondanelli M, Ferrari      E, Herrera      CJ, Cestaro      B, Lombardo      A, Venerando      B, Erythrocyte membrane alterations during      ageing affect beta-D-glucuronidase and neutral sialidase in elderly      healthy subjects. Exp Gerontol 2005; 40(3): 219-25.
  4. http://www.ncbi.nlm.nih.gov/pubmed/?term=alterations+during++++++ageing+affect+beta-D-glucuronidase+and+neutral+sialidase+in+elderly++++++healthy+subjects.
  5. Jha R, Rizvi SI, Age-dependant  decline in erythrocyte acetylcholinesterase activity: correlation with oxidative stress. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2009; 153(3):195–8.
  6. http://www.ncbi.nlm.nih.gov/pubmed/19851431
  7. Kaizer RR, Correa MC, Gris LR, Da Rosa CS, Bohrer D, Morsch VM, Schetinger MR, Effect of long-term exposure to aluminum on the acetylcholinesterase activity in the central nervous system and erythrocytes. Neurochem Res 2008; 33(11):2294-301.
  8. http://www.ncbi.nlm.nih.gov/pubmed/?term=Effect+of+long-term+exposure+to+aluminum+on+the+acetylcholinesterase+activity+in+the+central+nervous+system+and+erythrocytes.
  9. Klajnert B, Sadowska M,      Bryszewska M, The effect of polyamidoamine dendrimers on human erythrocyte membrane acetylcholinesterase activity. Bioelectrochem 2004; 65(1): 23-6.
  10. http://www.ncbi.nlm.nih.gov/pubmed/?term=The+effect+of+polyamidoamine+dendrimers+on+human+erythrocyte+membrane+acetylcholinesterase+activity.
  11. Lewandowski MH, Annual changes of circadian acetylcholinesterase activity in the brain stem compared to locomotor activity of the mouse under LD 12/12. J Interdisiplinary Cycle Res 1990; 21 (1): 25-32.
  12. http://www.tandfonline.com/doi/abs/10.1080/09291019009360023?journalCode=nbrr19
  13. Li Y, Camp      S, Rachinsky TL, Getman D, Taylor P, Gene structure of mammalian acetylcholinesterase. Alternative exons dictate tissue-specific expression. J Biol Chem 1991; 266(34): 23083–90.
  14. http://www.ncbi.nlm.nih.gov/pubmed/?term=Gene+structure+of+mammalian+acetylcholinesterase.+Alternative+exons+dictate+tissue-specific+expression
  15. Marchiafava PL, Longoni B, Melatonin as an antioxidant in retinal photoreceptors. J Pineal Res 1999; 26(3): 184-89.
  16. http://www.ncbi.nlm.nih.gov/pubmed/10231733
  17. Molochkina EM, Zorina OM, Fatkullina LD, Goloschapov AN, Burlakova EB, H2O2 modifies membrane structure and activity of acetylcholinesterase. Chem Biol Interact 2005; 157-158(1): 401-4.
  18. http://www.ncbi.nlm.nih.gov/pubmed/?term=H2O2+modifies+membrane+structure+and+activity+of+acetylcholinesterase.
  19. Moudgil VK, Kanungo MS, Effect of age on the circadian rhythm of acetylcholinesterase of the brain of the rat. Comp Gen Pharmacol 1973; 4(14):127-30.
  20. http://www.ncbi.nlm.nih.gov/pubmed/4770270
  21. Prall YG, Gambhir KK, Ampy FR, Acetylcholinesterase: an enzymatic marker of human red blood cell aging. Life Sci 1998; 63(3): 177-84.
  22. http://www.ncbi.nlm.nih.gov/pubmed/?term=Acetylcholinesterase%3A+an+enzymatic+marker+of+human+red+blood+cell+aging
  23. Rizvi SI, Chakravarty S, Modulation of acetylcholiesterase activity by melatonin in red blood cells. Acta Endocrinologica (Buc), 2011; 8(3): 311-16..





Read Full Post »