Vaccines : Alzheimer's Disease

Introduction :

Alzheimer's disease ( AD ) is a progressive degenerative brain disease - is the most common form of dementia. Dementia – in simple words – is the loss of intellectual and social abilities.

Most of the research in this field is done in the USA, which shows that presently more than 4 million Americans suffer from AD. This figure is expected to go up more than thrice – to about 14 million – within 20 years. Although until now there is no definitive treatment or prevention for AD, tremendous progress has been made recently in this field.

Image : Ronald Reagan, once the president of the US and the person who defused the cold war by initiating the START I and START II treaties, has Alzheimer's. He no longer remembers his wife's name or  recognizes who she is.

I don't know anything about Alzheimer's!

Don't worry. I knew even less than you do before I wrote this article. But to understand the mechanism in which the vaccine will  be effective, it is necessary to know a bit about the pathology of AD.

 
There are many theories explaining the triggering factors for AD. Most commonly believed risk factors include – 

1) Genetic : Chromosomes 1, 14, 19 and 21(trisomy) being incriminated, 
2) Head injury
3) A part of the general aging process : AD is usually seen above 65 yrs, 
4) Others : include viral infection, hypothyroidism, depression, parental age and non-smoking!

There is diffuse cerebral atrophy with widening of cerebral sulci – the occipital lobes being spared in most cases.  There is compensatory ventricular enlargement (hydrocephalus ex vacuo).

Image :Alz-affected brain at the top and a normal age matched brain below it. Not the decrease in size of the affected brain and the corresponding prominent sulci.

In Alzheimer's deposition of amyloid in the brain is found in a typical plaque which is known as a senile plaque. A closer look at the amyloid in these plaques is warranted, since it is the basis for the vaccine under development.

The senile plaques are composed of focal collections of dilated, tortuous, neurites that often contain paired helical filaments (PHF) arranged around a central core. This core is composed primarily of a specific and unique molecule, the beta-amyloid peptide.

Image : Please click on the image to view a  bigger, clearer image with a short description.

The beta peptide is a fragment of a much larger amyloid precursor protein (beta-APP), the normal function and source of which are not yet known.
The deposition of amyloid appears to be a very early, perhaps the first, event in the pathogenesis of AD. The plaques accumulate to neurotoxic levels, compressing those nerve fibres that lie in their path, effectively destroying these regions of the brain. This destruction of cerebral tissue then causes the behavioral changes that we associate with AD.

Image : MRI of Alz-Affected brain. The pointer shows the macroscopic collection of amyloid.

So... How does the vaccine work??

The vaccine for AD is made up of a fragment of the amyloid precursor protein (APP) – which is deposited as senile plaques, as discussed earlier.

From the knowledge gathered from the animal models so far, the mechanism of working of the vaccine is as follows –

Although, predominantly it is humoral immunity, but a role of cell mediated immunity cannot be ruled out as well.

Thus, the widespread amyloid deposition, activation of microglia and presence of NFT in AD might be amenable to a therapeutic vaccination stratagem that is designed to prevent the deposition of  beta amyloid peptide in plaques or tau in NFT in the first place or, once present, to rid the brain parenchyma of extracellular amyloid and intracellular NFT.

Some Caveats :

***The exact immunomodulators involved in this process have not been found out as yet. For example, circulating, local and plaque-bound cytokines, chemokines, compliment and compliment inhibitors have not been well studied in any of the animal models.

***For the development of truly effective AD vaccines, there is also a need to know more about the factors that control the activation and proliferation of the key cell types involved with the immune response to AD -  target antigens, and their effects on amyloid and NFT clearance as well as on brain and cognitive function.

***Also, the research trials in rats/mice show a decrease in the amyloid deposition. Whether that actually amounts to stopping/reversing the disease process itself is not yet known.

Role of the vaccine :

 Although the exact cause of AD still remains elusive, the vaccine developed against AD is directed against preventing, delaying or reversing the formation of AD-associated lesions. Recent results, using the transgenic mouse model, have suggested that immunological interventions can retard and even reverse the development of at least some of the pathological changes of AD, and thus alleviate the symptoms associated with the disease.

- Mukesh Sharma
Comments ? Suggestions ? Additions? Please email mukesh@kemates.com

Additional notes :

Pathogenesis :

Besides senile plaques, two other abnormalities are noticed in the microscopic sections of most Alz-affected brains :

1)Neurofibrillary tangles : The integrity of brain neurons depends on the normal functioning of a protein called tau. In AD threads of tau get altered which causes them to become twisted and form tangles within the neurons. These highly insoluble tangles are believed to cause death of the neurons.

Image : The arrow points to a neurofibrillary tangle. Please click on the image to view a larger version

2)Amyloid angiopathy : of subarachnoid and cortical arteries of the brain is also a frequent accompaniment.