Beta-Amyloid Plaques and Tau in the Brain

Don’t Forget About Alzheimer’s Medicine!

Alzheimer’s, a neurodegenerative progressive disease, is the most common cause of dementia. Early-onset is autosomal dominant, while late-onset Alzheimer’s disease is multi-factorial. ApoE4 allele is associated with late onset and sporadic forms of Alzheimer’s. The allele also increases the risk for genetic form of Alzheimer’s. Individuals with ApoE2 allele exhibit protection against Alzheimer’s, while suffering from type III hyperlipoproteinemia. The disease is primarily known to be caused by accumulation of beta-amyloid. Normally, amyloid precursor protein (APP) is cleaved to beta-amyloid by beta secretases and gamma-secretase, which is encoded on the presenilin (PS) 1 & 2 genes. The beta-amyloid protein is modified further to prevent clumping of the proteins. Patients with early-onset Alzheimer’s have a mutation in the APP gene, PS1 or PS2 genes. As the APP gene is located on chromosome 21, individuals with Down syndrome make more beta-amyloid and are at a higher risk of developing Alzheimer’s. In addition to beta-amyloid plaques, that form extracellularly, neurofibrillary tangles are another hallmark of Alzheimer’s. These tangles are clumps of hyperphosphorylated tau protein inside the neurons. Tau is a microtubule associated protein that stabilizes microtubules by inhibiting depolymerization of the microtubule dimers.

The most common approach to treat the disease has been to target the beta-amyloid protein plaques forming in the brain. Individuals present with symptoms of Alzheimer’s years after the formation of beta-amyloid plaques. This could likely be the reason why so many drugs fail to be effective. According to Dr. David Holtzman, “there’s no question that science says beta-amyloid is important in the disease. The question is when can it serve as a treatment?” 

In February 2020, Eli Lilly announced the failure of solanezumab, an anti-amyloid drug to treat autosomal dominant Alzheimer’s. Gantenerumab is another anti-amyloid medicine for genetic form of Alzheimer’s that recently failed in clinical trials. The ineffectiveness and failures in clinical trials of drugs have caused some scientists to consider approaches that are not only aimed at amyloid. Dr. Karen Duff is a researcher and a professor at Columbia University that has been working on treatment for Alzheimer’s for over 15 years. Her lab focuses on understanding four concepts that could potentially be drug targets: “the propagation of disease through the brain; the impact of ApoE4 on disease risk; the impact and restoration of functional clearance mechanism; and the basis and manipulation of memory deficit.” Some scientists, including Dr. Duff, share the idea that neurofibrillary tangles formed by tau may play a more significant role than beta-amyloid. Others, such as John Hardy, strongly believe in the amyloid-hypothesis. He believes that protein plaques cause damage to neuron cell membranes and if microglia cells fail at their immune function to remove the faulty cell membrane protein, the cell membrane wouldn’t be able to clear beta-amyloid and the plaques built up more and cause more damage. His idea was backed by genome sequencing that identified genes that associated with late-onset Alzheimer’s, many of which were involved in microglial metabolism.

Abnormal Tau
Abnormal Tau. Credit: National Institute on Aging, NIH via NIH Flicker. CC BY-NC 2.0

While the scientific community and those affected by this disease wait for a cure, there are therapies that can potentially alleviate the symptoms associated with Alzheimer’s. Colinesterase inhibitors are a common approach to help patients suffering with mild to moderate Alzheimer’s. Galantamine, rivastigmine, donepezil are few of the FDA approved drugs that reduce symptoms of Alzheimer’s. Colinesterase inhibitor prevent clearance of acetylcholine, a neurotransmitter believed essential for memory and thinking. Over time these inhibitors also cease to function since there is less acetylcholine produced in individuals with Alzheimer’s due to the damage caused to the brain. Peroxisome proliferator-activated receptor (PPAR) gamma is shown to be elevated in the brains of Alzheimer’s patients. PPAR gamma, when stimulated, function in glucose and lipid metabolism and modulate inflammation by inhibiting genes associated with inflammation. Cannabis, an agonist of PPAR gamma, can be used therapeutically. Thiazolidinedione (TZDs), such as rosiglitazone and pioglitazone, are another class of PPAR gamma agonist. These are FDA approved drugs for diabetes, but are currently being explored as potential therapy for Alzheimer’s.

References:

How Is Alzheimer’s Disease Treated? (2018, April). Retrieved from https://www.nia.nih.gov/health/how-alzheimers-disease-treated Karen E. Duff, PhD. (2020, April 27). Retrieved from https://www.pathology.columbia.edu/profile/karen-e-duff-phd

Khan MA, Alam Q, Haque A, et al. Current Progress on Peroxisome Proliferator-activated Receptor Gamma Agonist as an Emerging Therapeutic Approach for the Treatment of Alzheimer’s Disease: An Update. Curr Neuropharmacol. 2019;17(3):232‐246. doi:10.2174/1570159X16666180828100002. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425074/

Kim SH, Yang JW, Kim KH, Kim JU, Yook TH. A Review on Studies of Marijuana for Alzheimer’s Disease – Focusing on CBD, THC. J Pharmacopuncture. 2019;22(4):225‐230. doi:10.3831/KPI.2019.22.030. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970569/

Lewis, T. (2020). A Harder Look at Alzheimer’s Causes and Treatments. Retrieved from https://www.scientificamerican.com/article/a-harder-look-at-alzheimers-causes-and-treatments/

Pérez MJ, Quintanilla RA. Therapeutic Actions of the Thiazolidinediones in Alzheimer’s Disease. PPAR Res. 2015;2015:957248. doi:10.1155/2015/957248. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637502/

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