NOTICE: Posting schedule is irregular. I hope to get back to a regular schedule as the day-job allows.

Wednesday, February 8, 2012

The GUIDE: What is Alzheimer's Disease? [Full link to blog for email clients.][FT:C44]

This post gets directly at a question asked a couple of weeks ago, in terms of exactly what Alzheimer's Disease (AD) is in terms of a neural disease.  Knowing what the actual disease process is, coupled to a discussion of what brain areas and neuron types are affected, will help to explain many of the effects. 

To start out, I am going to bring back the illustration from last blog, and explain what is going on.
PubMed Health. A service of the National Library of Medicine, National Institutes of Health.
Illustration URL:
  In short, AD is a disease in which certain types of neuron die due to an accumulation of proteins that are normally broken down and metabolized.  Instead of being broken down, the proteins accumulate both within neurons and "plaques" of dead and dying cells.  These dense masses also exert pressure on other neurons and cause problems due to impaired blood and circulation and "lymph" flow (in brain, it's not really lymph, but a thinner, filtered electrolyte solution called "Cerebrospinal Fluid").

I will digress for but a moment - many if not most cells in the body are round or squarish shapes, but neurons have long branches called dendrites (from the Latin for tree) and even longer axons which connect neurons together in a manner similar to electrical wiring. Forming and maintaining this shape requires an internal structure, and that is provided by very fine filaments and tubes called, unsurprisingly,neurofilaments and neurotubules.  These structures form what is common called the "cytoskeleton" and are responsible not just for holding the cell's shape, but for providing a transportation pathway for movement of chemicals throughout the neurons. Under normal circumstances, the neurofilaments consists of polymer chains of a protein called "Tau."  In the AD brain and certain other neural disorders, Tau proteins do not assemble properly, and the neurofilaments become tangled and random.  These tangles can be seen when the brain tissue is examined under a microscope, and excess Tau can be detected both in the AD brain and in tissue where cell damage has occurred.  Thus it is not entirely clear whether the AD-affected neurons make too much Tau, or simply that excess Tau is available due to death of neurons and attempts to make more  and appropriate neurofilaments for the neurons.

The membranes of cells in the body consist mostly of lipid molecules with a few proteins floating in the lipid.  Think of how a soap bubble forms, trapping air inside of a thin film of detergent, with swirls of color and pattern in the soap.  Now think of the appearance of oil on water.  That same swirl of color indicates that a thin film of oil - lipid - is dispersed over the surface of the water.  Shake the mix, and you will see tiny bubles of oil, some with water trapped inside.

Cells are like that, a thin film of lipid, with water and proteins on the inside, salt water on the outside, and proteins plus complex oily molecules (triglycerides and cholesterol!) to stabilize the film of lipid into a membrane.  One of the stabilizing proteins that is particularly important to forming the synapses which connect neurons, is amyloid precursor protein (APP) is important, but when excess APP is produced, it can be broken down into fragments of "beta-amyloid" which are insoluble and difficult to metabolize.  Deposits of beta amyloid accumulate and essentially "choke" neurons.  As neurons die, the beta-amyloid remains and builds up, leaving "plaques" and dead neurons in the brain in place of healthy neurons.

AD is characterized by the presence of neurofibrillary tangles - indicating cells that are nonfunctional or dying - and plaques, indicating large ares where many neurons have died.  Neurons do not regrow, and the accumulations of Tau and beta-amyloid are dense, so the total brain volume shrinks.  Once this process occurs, the symptoms match the brain areas most affected - temporal lobe plaques are associated with memory problems, frontal lobe with decision-making and movement planning, parietal and occipital lobe with sensory inputs and hallucinations, the "basal nuclei" with movement disorders and all of the above.

Thus the many symptoms of AD can be explained by examining the progress of the disease - AD tangles and plaques typically show up in temporal lobe, then parietal/frontal lobes and finally thalamus and the deep nuclei - resulting in amnesia, then personality changes, difficulty making decisions, and gradual worsening of all of the above.

An additional consideration that had neuroscientists chasing in the wrong direction for a few years is that the initial stages of the disease appear to preferentially affect that neurons that use acetylcholine for neurotransmitter.  You may recall that there the most common chemicals associated with communication between neurons are (in order of prevalence)glutamate, gamma-amino-butyric acid, norepinephrine, and acetylcholine (ACh).  ACh does double duty by also being the neurotransmitter that is present in muscles and forms the junction between motor nerve (for control of muscles) and the muscle itself.  ACh is also very prevalent in the hippocampus, and is associated with memory storage and recall processes.  AD was origianlly thought to be a disease solely of ACh neurons, and thus could be treated much the same as Myasthenia Gravis - a disease of the ACh receptors in muscles.  Alas, AD affects all types of neurons, but the presence of many ACh neurons in the hippocampus associated with the early symptoms of the disease do make it a candidate for treatment drugs.

The next blog will discuss treatment and therapeutic options, and perhaps provide a bit of hope for the future in the treatment of AD.

Thanks for reading.

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