Week 4: Taking a Step Back

Apr 08, 2020

Hey everyone! It has been a few weeks since my last post and in that time I have “taken a step back” from my original research question. Now, don’t get me wrong, I am still investigating the original question. However, I’ve realized that while researching the connection between cardiovascular abnormalities and the emergence of Alzheimer’s disease, it’s helpful to also explore AD on its own. Gaining a better understanding of the disease may give me a better understanding of how increased blood perfusion could possibly lead to AD.

When Alois Alzheimer’s first studied the disease in the early 20th century, he discovered two forms of pathology: senile plaques and neurofibrillary tangles. Senile plaques are made of an amyloid core with astrocytes, axons, and dendrites surrounding the material. Neurofibrillary tangles are made mainly of hyperphosphorylated tau. The amyloid cascade hypothesis states that the pathogenesis of AD is the accumulation of toxic amyloid followed by “inflammation, neuritic and synaptic changes, neurofibrillary tangles, neurotransmitter loss, gliosis, and dementia.” Since amyloid is present in the brain 15-20 years before AD even emerges, there has been considerable research toward intervening in the cascade to target the production of amyloid.

Amyloid-directed treatments are of two types. Secretase inhibitors block the formation of Aß by targeting the enzymes that help yield the toxic form of amyloid. Anti-aggregants prevent the accumulation of amyloid monomers.

  1. Secretase Inhibitors – It is important to note that Aß is cleaved from the larger APP precursor protein. The enzymes α-secretase and then γ-secretase help form sAPP α. In abnormal processing, ß-secretase and γ-secretase to form toxic ß-amyloid proteins. From this standpoint, secretase inhibitors seem like the most promising solution to preenting the emergence of AD. However, trials of the drug semagacestat demonstrated that γ-secretase inhibitors actually worsened the conditions of patients. This brought into question how effective secretase inhibitors could be.
  2. Anti-Aggregants

When ß-amyloid is cleaved it forms several monomers that are not on their own toxic. However, as they combine into clusters to form oligomers through aggregation they deposit themselves as plaques. The video below helped me understand the process!

www.youtube.com/watch? v=73PRA7wUqS0

Preventing the aggregation of ß-amyloid is yet another point of intervention for researchers looking for drugs to prevent or slow AD. The Canadian company Neurochem experimented with this through clinical trials of their drug, Alzhemed. Analysis of the CSF found that there were lower amounts of ß-amyloid however there was no reduction in cognitive decline in patients with AD. Another approach involves reducing other, less harmful amyloid types such as APOE before aggregation through cholesterol-lowering drugs. Wolozin et al. in 2004 shows that individuals who took drugs targeted at reducing hypercholesterolemia had lower risk of AD in the future.

 

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So that seems to be the extent of amyloid-directed treatments. However, there is more current research being done towards preventing the formation of neurofibrillary tangles. I’ll be continuing my research into disease therapy to get a better understanding of AD next week!

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