GCR: Alzheimer's Disease

The hallmark neurohistological changes observed in AD are the presence of neurofibrillary tangles (NFT) and b-amyloid neuritic plaques.

Plaques are dense, insoluble deposits of protein and cellular material outside of the neuron. Tangles are insoluble twisted fibers that accumulate inside of neurons. The formation of these abnormalities causes neuronal death. Current research activity is focused on interventions to prevent the formation of these lesions or arrest the process.

It is important to realize that the plaques and tangles are the end result of a complex neuropathologic cascade; the triggering event remains unknown.

In AD, plaques develop first in areas of the brain used for memory and other cognitive functions In the center of the neuritic plaques are amino acid segments called b-amyloid protein (bAP). bAP is cleaved from a much larger protein called amyloid precursor protein (APP) which is found in nerve cell membranes as well as in microglia (scavenger cells that secrete inflammatory mediators) and surrounding astrocytes. If APP is cleaved by a secretase, a soluble form of non-toxic bAP is the outcome. In the case of AD, abnormal cleavage of APP by the enzymes b and g secretase results in formation of the abnormal, insoluble bAP.

Next, the abnormal bAP aggregates into filaments outside the neuron and in combination with fragments of dead neurons, microglia, and astrocytes, forms neuritic plaques.

It has not been confirmed whether amyloid plaques themselves cause AD or whether they are just produced as a consequence of the AD pathology. In animal models, injection of b-amyloid into the brain appears to have a direct neurotoxic effect. Researchers believe that b-amyloid is toxic to human neurons also, perhaps by causing inflammation or by generating free radicals that could further mediate a cascade of neuronal death. In addition, researchers have confirmed that mutation of the gene that codes for APP on chromosome 21 is linked to early-onset, familial AD.¹

In a recent scientific breakthrough, Vassar and colleagues² reported that they had cloned a protease with all of the knowncharacteristics of b-secretase, one of the 2 proteases that are known to cleave APP into the pathologic form of b-amyloid found in the AD neuritic plaques. The investigators named this protease BACE (b-site bAPP-cleaving enzyme) and postulated that bACE inhibitors may represent a potential disease-arresting treatment for AD.

NFTs are seen as twisted cell "threads" inside neurons. Microscopically, NFTs appear as "flames" inside the cells.

The primary component of NFTs is tau protein. Tau protein is the structural support for the microtubules - the cells' transportation and skeletal support system. In AD, tau filaments undergo abnormal phosphorylation which prevents them from binding to the microtubules. The result is that the microtubles collapse. Without an intact system of microtubules, the neuron cannot function, and eventually dies.