All of you know that cholesterol is synthesized locally in brain as well as peripherally in liver, both separated by a line of blood-brain barrier. But what about the case of hypercholesterolemia and how it eventually leads to increased amyloid depositions. what is the ultimate link between high serum levels of cholesterol and the Alzheimer's disease?
When high levels of cholesterol are attained in the periphery, the deposits accumulate in the blood vasculature, thus leading to atherosclerotic changes!
These deposits then lead to post- ischemic hypoperfusion, accumulation of inflammatory cytokines and hence all the further processes ultimately leading to breakdown of blood- brain barrier. The line of separation is thus disrupted which allows blood cholesterol to enter brain tissues.
Also, chronic hypoperfusion results in increased expression of BACE-1 (beta secretase-1) gene. This increases the concentration of A-beta fibrils and thus amyloid deposits!
The second pathway of causation is through Oxysterols which are oxidised derivatives of cholesterol. These metabolites contribute to the process of atherogenesis by:
- Foam cells formation
- Endothelial cell dysfunction
- Adhesion of circulating blood cells (mainly white blood cells)
- Apoptosis of vascular cells
Till here I have told you the direct effects of cholesterol on amyloids. Now lets talk about certain other pathologies in which the Alzheimer's disease is associated with high cholesterol :-
Firstly, hypercholesterolemia may predispose to the Alzheimer's disease by comorbid Type- 2 Diabetes mellitus !!
High blood sugar due to insulin resistance does harm to the brain in several ways, as mentioned:
- damage blood vessels
- chemical imbalance (due to excess insulin)
- local inflammation
This increases the risk of the Alzheimer's to a great extent !!
Secondly, in cases of Familial hypercholesterolemia in which there is a hereditary predisposition to high levels of serum cholesterol, the pathways of causation of alzheimer's disease are :-
- alterations in metabolism of Beta- peptide
- effects on synaptic transmission
- decrease in cholesterol metabolism in the CNS !!
Thirdly, mutations in ABCA 1 gene of the ATP- binding casette- transporter (ABCA) family are associated with Tangier disease or, if less severe, with familial HDL- deficiency. (both characterised by low serum levels of HDL- cholesterol and accumulation of cholesterol esters in peripheral tissues.
Does every hypercholesterolemic person (or patient) has a high risk of predisposition to Alzheimer's disease in old age?
No! A lot many years back it was shown that the Apolipoprotein E allele E4 enhances the risk of late- onset familial and sporadic AD and thus increases beta- amyloid deposition in brain!
How does it lead to the process?
1. It impairs glia-to-neuron transport of cholesterol
2. decreases degradation of amyloid deposits
3. high LDL- cholesterol levels in blood
4. aids in atherogenesis.
> Mutations in lipid metabolism- related proteins Apo J /Clusterin (CLU) and ABCA 7 are risk factors for AD. ( Normally, these proteins are involved in lipid transport and regulate apoptosis, immunoglobulin interactions, and complement defense. )
For treatment of cholesterol- induced Alzheimer's disease, click here.
Thats all! (quite an interesting post.. isn't it? :p )
- Jaskunwar Singh