Alzheimer's Disease

Summary

By the age of 60, patients who suffer from Alzheimer’s (ALZ) disease can forget to speak, feed themselves, dress themselves, and go to the bathroom. ALZ and other dementias cost the United States $259 billion in 2017 and affect more than 5 million Americans. The Alzheimer’s Association estimates that by 2050, 16 million Americans will be affected by this disease. Being the sixth leading cause of death in the United States, the pursuit for the cure of ALZ is one of the most important focusses in medical research.

ALZ is a progressive brain disorder defined by the death of brain cells leading to memory loss and other brain function impairment. Patients suffering with ALZ are required to live with a caregiver to perform simple tasks. Notable features in the brain are associated with ALZ. The first characteristic of an ALZ affected brain is the buildup of plaques, which are clumps of beta-amyloid protein fragment. Another feature associated with ALZ is the presence of tangles, which are made of strands of abnormal tau protein. The two other features associated with ALZ are inflammation and death of brain cells, which are usually a result of the first two features.

ALZ is a genetic disease associated with mutations in chromosomes 21, 14, and 1. These mutations cause the formation of abnormal proteins. One specific protein that is highly linked to Alzheimer’s disease is an abnormal Amyloid Precursor Protein (APP). This proteolysed protein forms beta-amyloid, which clump into plaques. These plaques block cell to cell signaling in the central nervous system and result in the symptoms of ALZ such as dementia, delusion, disorientation, confusion, inability to critically think (i.e. solve problems), and eventually to loss of involuntary motor skills. The cause of the formation of abnormal APP is a heavily researched topic and can be a potential target in a cure.

Signaling Pathway

Symptoms

The symptoms for Alzheimer’s Disease includes:

Dementia
Cognitive impairment (memory and perceptual loss)
Neurofunctional impairment (language, motor functions, coordination)
Depression
Mood swings
Rambling speech
Trouble with sentence formation
Hallucinations
Loss of voluntary muscle control (bladder)

The central nervous system is responsible for all functions, thoughts, and behaviors carried out by humans. The brain is where stimuli are transduced and where signals are sent to other organs to develop a response. Destruction of the brain or blockage of pathways where signals are transduced effect many of the pathway sin the brain that explain the symptoms above. Blockage of the reward pathway would likely be the cause of depression and mood swings. Blockage of motor control pathways would result in loss of muscle control. Destruction in Wernicke’s and Broca’s area would result in the rambling speech and trouble with sentence formation. Destruction or blockage of signals in the hippocampus would result in dementia. Destruction of the prefrontal cortex would result in the most troubling of symptoms, overall cognitive impairment.

Therapies

Although the only current therapies are symptom management medication, cholinesterase inhibitors and NMDA receptor antagonists are currently prescribed medication used in combination to treat ALZ.

Cholinesterase inhibitors. Acetylcholine (ACh) is a neurotransmitter that is used at the neuromuscular junction. This neurotransmitter is what activates muscle cells and allows for muscular contraction. Acetylcholinesterase (AChE) is an enzyme that breaks down acetylcholine into choline and acetic acid. This is what terminates synapse transduction. In patients with ALZ, as neurofibular tangles prevent ACh from binding to its receptors, its best to keep the levels of Ach as high as possible to maintain some muscular function, as usually not every single Ach receptor is blocked. In order to achieve this, cholinesterase inhibitors bind to AChE and prevent the breakdown of ACh, to allow for some form of neuromuscular function.

NMDA (N-methyl-D-aspartate) receptor antagonist. In patients with ALZ, death of neuronal cells results in excess release of the excitatory neurotransmitter glutamate. This results in excessive amounts of signals being transduced and can cause more neurons to die. Glutamate binds to NMDA receptors. Preventing the binding of excess glutamate into healthy neurons can prolong the survival of the brain of a patient with ALZ.

Identification of Targets and Potential Side Effects

Multiple targets can be sought after in the cure for ALZ. Beta secretase inhibition (enzyme that modifies APP into beta amyloid), would result in no proteolytic cleavage of APP into beta amyloid and thus result in the formation of no neurofibular tangles. There are a number of beta amyloid degrading enzymes that have been identified, including neural endopeptidase and insulin-degrading enzyme. Increased expression of these enzymes may result in higher beta amyloid degradation.