Alzheimer's disease and cholesterol

Dementia

Umbrella term for impairement of cognitive functions/end stage of neurodegenerative diseases

Alzheimer’s

Specific form of dementia and most common neurodegenerative disorder (35mil)

Symptoms

Progressive impairment of spatial orientiation, memory, language + personality stage

Sign of AD

Amyloid plaques in the brain = brain is 30% lighter in end stage

Treatment status

No effective treatment but approved therapeuthic antibodies

Strongest genetic risk factor for AD

Mutations/variant of ApoE4

1st criterion for a good drug target

Disease engagement or the evidence that the drug will be disease-modifying: changing the ApoE4 gene alters disease risk

2nd criterion for a good drug target

Drugability or the evidence that the drug can reach and act on the target

Includes knowing the side effects, if a natural compound is an option and if a known compound could be optimized

3rd criterion of a good drug target

Selectivity or the evidence that the target should not be expressed at high levels everywhere in the body

Alternate approach

Instead of analyzing what causes AD in families with increased cases → Analyze what prevents the disease in populations with no disease

CETP

• Cholesteryl esther transfer protein

• Associated with longevity, good memory+cognitive functions in centenary populations

What kind of molecule is CETP?

1. Serum glycoprotein secreted predominantly by the liver, kidney, spleen, bloodstream

2. Linked to high LDL-Cholesterol (bad)

Model used to test hypothesis

Transgenic mice bc they do not express CETP = low LDL observed

Result of transgenics

Cholesterol increased shown by Mass spectrometry and Filipin III fluorescence

CETP activity and AD

Low activity CETP leads to higher chances of Alzheimer’s disease free survival

Drug repurposing

Def: Reusing a drug/compound for a different disease

Advantages: Accelerates the process of finding bc phase I (toxicity testing) is likely alr completed + Saves money and time

Ex: Metmorphin #1 (type II diabetes → breast cancer)

Repurposed drug for AD

Evacetrapib (CETP inhibitor)

Pharmacokinetic studies

Allow to evaluate whether a drug crosses the BBB (0.5 h after 40mg/kg)

How is low CETP activity recorded in studies?

By a low lipid transfer in the presence of Evacetrapib

CETPtg

Mice that express human CETP = high CETP = high LDL = fast progressing AD

APPtg mice

Mice that overexpressed human amyloid precursor proteins = plauqe = simulated AD

Evacetrapib and Novel Object Recognition

Increased

Contradictory result

Cholesterol levels where higher in mice with Evacetrapib (fluorescence)

Whta did RNAseq reveal ab the activity of CETP inhibition?

That it primarily regulated genes that are connected to endothelial health anf functioning rather than neuronal pathways

Then why is it that data shows that CETP affects the brain?

The data likely shows that CETP acts by maintaining endothelial health in the brain (2-5%)

Proof/data

Higher CETP in CSF correlated with decreased levels of endothelial marker protein