What Causes Amyloid Plaques in Alzheimer’s disease?

Amyloid plaques is one of the main characteristic findings in those suffering from Alzheimer’s disease. The other main characteristic feature of Alzheimer’s disease is Neurofibrillary tangles.

Today we will focus mainly on the causes of Amyloid plaques formation in Alzheimer's disease.

Before discussing the causes of Amyloid plaques formation, let's cover some basic background information.

You should also read:

• What are the treatment options for Alzheimer’s disease? 
• Caring for a parent with Alzheimer’s disease
• Can Alzheimer's Disease be Cured?

What is an amyloid (protein)? What are amyloid plaques?

Amyloids are basically abnormal proteins which have the ability to group together to form large clusters of proteins called Amyloid plaques. In humans, amyloids are usually abnormal proteins and their function is not well understood. In very simple terms, they are formed by defective breakdown of normal proteins. Under normal conditions, the body has the ability to remove these proteins but in Alzheimer’s disease these proteins aggregate and cause damage to brain cells.

What is amyloidosis?

The abnormal amyloid proteins get deposited in various organs including the brain and this can lead to a variety of diseases which are collectively called amyloidosis. For example, deposition of amyloids in the kidney can lead to nephrotic syndrome and in the heart it can cause heart failure. In the brain it can cause neurodegenerative diseases like Alzheimer’s disease.

What are the types of amyloid proteins? 

There are different types of amyloid proteins and each one of them is linked to different diseases. In Alzheimer’s disease the amyloid protein that is the main culprit is called the Beta Amyloid protein.

The table below shows the different types of amyloids along with their associated disease / amyloidosis.

Amyloid Type	Associated Disease / Amyloidosis
β2 microglobulin	Haemodialysis-associated amyloidosis
β amyloid	Alzheimer disease
Transthyretin	Senile systemic amyloidosis, familial amyloid polyneuropathies, leptomeningeal amyloidosis
Serum amyloid A protein	Systemic inflammation
Prolactin	Prolactinoma
Prion protein	Prion diseases
Oncostatin M receptor	Primary cutaneous amyloidosis
Lysozyme	Familial visceral amyloidosis
Leukocyte cell derived chemotaxin-2	LECT2 amyloidosis
Keratoepithelin	Familial corneal amyloidosis
Integral membrane protein 2B	Cerebral amyloid angiopathy
Gelsolin	Finnish type amyloidosis
Fibrinogen alpha chain	Familial visceral amyloidosis
Cystatin C	Cerebral amyloid angiopathy
Calcitonin	Medullary carcinoma of the thyroid
Atrial natriuretic factor	Senile amyloid of atria of heart
Apolipoprotein A1	Familial visceral amyloidosis
Amyloid light chain	AL amyloidosis / multiple myeloma
Amylin	Type 2 diabetes.

Table: Different types of amyloids along with their associated disease / amyloidosis

How do beta amyloid proteins produce amyloid plaques?

Beta Amyloid proteins have the ability to clump together and form larger chunks which are called Amyloid plaques. In technical terms, this occurs because the beta amyloid proteins become abnormally folded into particular shapes which causes other beta amyloid proteins to become misfolded and stick to it. This sticky nature of beta amyloid proteins ultimately causes the beta amyloid plaque formation in Alzheimer's disease.

How do Beta Amyloid protein plaques cause Alzheimer’s disease? 

Beta Amyloid protein plaques are toxic to nerve cells and are thought to cause interruption in the signal transmission between neurons. They also cause structural damages to the nerve cells which ultimately cause death of the nerve cells and progression of Alzheimer’s disease.

A study that was done by the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND) suggests that beta amyloid plaques cause the level of calcium inside the neurons to rise to a dangerous level which leads to the interruption in signal transmission between neurons. Increased levels of calcium inside neurons is also associated with neuronal cell damage. The calcium related cell damage is mediated by an enzyme called calcineurin and it is found in another study that blocking this enzyme by a calcineurin inhibitor may improve cognitive abilities. However, both of these studies were conducted using Alzheimer’s mouse models and data obtained using animal models do not completely reflect the disease pathology in humans but this does open doors for further research into whether calcineurin inhibitors could be used in the treatment of Alzheimer’s disease.

How do beta amyloid plaques cause the calcium level to rise inside nerve cells? 

The exact mechanism has not yet been discovered. However, scientists do suggest that the beta amyloid proteins plaques form membrane ion channels on the nerve cells. These ion channels in turn allow calcium ions to enter the nerve cells completely unregulated which ultimately causes neural signal disruption and cell death.

So, what causes beta amyloid plaque production in Alzheimer’s disease? 

The beta amyloid proteins are formed by the breakdown of larger proteins called Amyloid precursor proteins. These amyloid precursor proteins are broken down by enzymes called alpha, beta, and gamma secretase. When amyloid precursor proteins are broken down by the beta and gamma secretase enzymes they produce shorter segments of proteins called beta amyloids. Some of these beta amyloid proteins are abnormally folded and it is now believed that these misfolded beta amyloid proteins cause other beta amyloid proteins to become misfolded and stick together which ultimately cause large chunks of beta amyloid plaque formation which ultimately leads to Alzheimer's disease.

Let’s look at a few risk factors and possible ways how abnormal beta amyloid plaques are produced in Alzheimer’s disease:

1. Age 

Age is the single most important risk factor in Alzheimer’s disease. The older someone is, the more beta amyloid plaques that person is likely to have. Scientist now believe that plaque formation and build up occurs well before the signs and symptoms of Alzheimer’s appear.

2. Genetic defects

Alzheimer’s disease is a multi-factorial disease and genetics play some important roles in the development of the disease. Some specific genetic defects may cause Alzheimer’s disease to occur early (30 to 60 years) and recurrently in families and this variety of the disease is called the Early onset familial Alzheimer’s disease. Genetic defects may also cause Late onset Alzheimer’s disease(>65 years).

Genetics of Early onset familial Alzheimer’s disease

Early onset familial Alzheimer’s disease is associated with defective genes in the chromosomes 1, 14 and 21. Genes in these chromosomes normally produce proteins which play important roles in the breakdown of Amyloid precursor proteins but since they are defective they produce defective proteins which cause abnormal breakdown of amyloid precursor proteins and increased production of beta amyloid proteins and plaques.

Genetics of Late onset Alzheimer’s disease

Late onset Alzheimer’s disease is associated with the Apolipoprotein E gene which is located on the chromosome 19. This gene produces the protein Apolipoprotein E which normally is the main carrier protein for cholesterol and other fats in the brain.

Apolipoprotein E protein also plays important roles in the breakdown and removal of the beta amyloid proteins. There are three types of Apolipoprotein E protein: APOE ε2, ε3, and ε4. The APOE ε4 variety is mostly associated with Alzheimer’s disease because it cannot effectively breakdown and remove the beta amyloid proteins and plaques. This leads to amyloid plaque buildup and progression of Alzheimer's disease.

3. Coexisting genetic disorders like Down’s syndrome

Presence of other genetic disease like Down’s syndrome greatly increases the likelihood of a person developing Alzheimer’s disease. People with Down’s syndrome have an extra copy of chromosome 21 and this leads to an increased production of beta amyloid proteins and plaques.

4. Microbial Infection and Alzheimer’s disease 

This is an interesting theory which suggests that beta amyloid plaques are actually produced as defensive mechanism against microbial invasion! Mouse models capable of producing beta amyloid plaques were injected with bacteria and it was found that the mice developed amyloid plaques overnight and when the scientists looked inside the plaques they found that each one had a single bacterium inside it. Basically what scientists are suggesting is that to protect the brain from microbes like bacteria, virus and other pathogens an increased level of beta amyloid plaques are produced which trap the invading pathogen. But after that, these amyloid plaques are not removed effectively and fast-enough which leads to inflammation of the brain (neuroinflammation) and nerve cell damage which ultimately leads to the development of Alzheimer’s disease.

5. Neuroinflammation and Alzheimer's disease 

This is one of the prominent theories of today which suggests that inflammation of the nervous tissue or neuroinflammation is one the key players in the parthenogenesis of Alzheimer’s disease. Here deposition of beta amyloid plaques in nerve cells like microglia and astroglia causes them to release inflammatory chemicals which are thought to contribute to Alzheimer's disease progression and severity. Furthermore, microglial cells, which normally remove the beta amyloid plaques by phagocytosis,  in Alzheimer’s disease cannot function properly and can not phagocytose the beta amyloid proteins which results in amyloid plaque buildup.

It is even seen that systemic inflammation and obesity disrupts the immunological process of the brain and contribute towards the progression of Alzheimer’s disease. There is also some evidence that people who take non-steroidal anti-inflammatory drugs regularly are associated with decreased Alzheimer’s disease in later life.

What Causes Amyloid Plaques in Alzheimer’s disease?

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