Alzheimer’s disease is identified by two pathological hallmarks in the brain: senile neuritic plaques and neurofibrillary tangles. The senile neuritic plaques form when degenerating neurons aggregate into large clumps. The aggregates contain protein fragments known as amyloid β ( A β ) that are derived from amyloid precursor protein (APP). Normally, the precursor protein is digested by an enzyme in the endoplasmic reticulum to form a 40-amino-acid form called A β40 . In Alzheimer’s, the precursor is digested in the wrong spot, and an aberrant 42-amino-acid form (Aβ 42 ) is made instead ( Fig. 20.21 ). This form tends to aggregate into clumps. In addition to the clumps of neurons, neurofibrillary tangles form inside otherwise normal neurons. This occurs when tau , a protein associated with microtubules, starts forming helical aggregates. These tangles eventually kill the neuron, which relies on the microtubules (and tau) to ship neurotransmitters from the cell body to the dendrites.
Beside tau and amyloid β protein, several other proteins are implicated in the pathology of Alzheimer’s disease. The presenilins are transmembrane proteins found in the endoplasmic reticulum and Golgi apparatus. Mutations in presenilins may increase the secretion of the A β42 form of amyloid β. Whether or not the presenilins are the actual proteases that digest the amyloid precursor protein remains to be proven. In addition, mutant presenilins make the nerve cell more sensitive to apoptosis, although the mechanism is not understood. Mutations in the presenilin genes, presenilin-1 and presenilin-2 , are the most common defects in patients with familial Alzheimer’s disease. These defects also cause the disease to start earlier than usual. Another protein implicated in Alzheimer’s is apolipoprotein E. A specific allele of the gene for this ( e4) promotes the formation of plaques. If someone inherits this allele, he or she is more likely to develop Alzheimer’s after the age of 60.
The formation of senile neuritic plaques causes the nerve cells to die, and the patient loses the function of that region of the brain. When a plaque forms, the immune systemis alerted by soluble signals from nearby microglial cells. These cells are activated by the aggregation of amyloid β protein. Once the immune system is activated, the immune cells will kill more neurons by secreting proteins that activate the death receptor pathway of apoptosis. (The immune system plays a role in the progress of many neurodegenerative diseases.)
Because the role of amyloid β in plaque formation is a central aspect of Alzheimer’s disease, recent work to establish a treatment has focused on this molecule. Scientists have been able to produce an antibody that breaks up aggregates of amyloid β in mice. The antibody can be given to Alzheimer’s patients as a vaccine, and early clinical trials have shown that it has few to no side effects. Although the exact mechanism is unknown, clinical trials are under way to determine how effective the vaccine is in human Alzheimer’s patients. Potentially in 5 to 10 years a real treatment will exist for this devastating disease..
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