FAQS

Amyloid Plaques

In AD, plaques develop first in areas of the brain used for memory and other cognitive functions. They consist of largely insoluble (cannot be dissolved) deposits of beta-amyloid - a protein fragment snipped from a larger protein called amyloid precursor protein (APP) - intermingled with portions of neurons and with non-nerve cells such as microglia (cells that surround and digest damaged cells or foreign substances that cause inflammation) and astrocytes (glial cells that serve to support and nourish neurons). Plaques are found in the spaces between the brain's nerve cells. Although researchers still do not know whether amyloid plaques themselves cause AD or whether they are a by-product of the AD process, there is evidence that amyloid deposition may be a central process in the disease. Certainly, changes in the structure of the APP protein can cause AD, as shown in one inherited form of AD, which is caused by mutations in the gene that contains instructions for making the APP protein. Recent work has revealed much about the nature of beta-amyloid and the ways in which it may be toxic to neurons, the processes by which plaques form and are deposited in the brain, and ways in which the numbers of plaques can be reduced.

Neurofibrillary Tangles

The second hallmark of AD consists of abnormal collections of twisted threads found inside nerve cells. The chief component of these tangles is one form of a protein called tau. In the central nervous system, tau proteins are best known for their ability to bind and help stabilize microtubules, which are one constituent of the cell's internal support structure, or skeleton.

In healthy neurons, microtubules form structures like train tracks, which guide nutrients and molecules from the bodies of the cells down to the ends of the axon. Tau normally holds together the "railroad ties" or connector pieces of the microtubule tracks. However, in AD tau is changed chemically, and this altered tau twists into paired helical filaments - two threads of tau wound around each other. These filaments aggregate to form neurofibrillary tangles. When this happens, the tau no longer holds the railroad tracks together and the microtubules fall apart. This collapse of the transport system first may result in malfunctions in communication between nerve cells and later may lead to neuronal death that contributes to the development of dementia. Recent research has shed much light on this abnormal aggregation of tau protein and on the role that certain genetic mutations play in changing tau's structure and contributing to neurodegeneration.

TAU

One major diagnostic feature of AD is the formation of neurofibrillary tangles in susceptible nerve cells in the brains of persons with AD. Tangles are composed of tau-containing paired helical filaments. Since the discovery in 1998 that mutations in the tau gene cause FTDP-17, scientists have rapidly initiated experiments to try to understand how changes in the structure of tau or how altered levels of specific forms of tau could result in the abnormal production of paired helical filaments and death of neurons in this disease. Finding out how changes in tau structure cause paired helical filaments and neuron death in FTDP-17 will help scientists to understand the similar process in AD brains.

Two types of transgenic mice have been used to examine how tau is involved in this process. One type of mouse, created by scientists at the University of Pennsylvania School of Medicine, overproduced one of the six forms of human tau (Ishihara et al., 1999). The mice showed aggregation of tau resulting in loss of microtubules in the neurons as well as degeneration of axons. The mice had pathology similar to that seen in FTDP-17 and the amyotrophic lateral sclerosis/Parkinsonism-dementia complex of Guam. These findings suggest that these neurodegenerative diseases can result from altered expression of normal forms of tau.

A second type of transgenic mouse was created with one form of the human tau gene containing the most common human mutation causing FTDP-17 (Lewis et al., 2000). Investigators at the Mayo Clinic, Jacksonville, Florida, found that this mouse had problems with walking and other movements and had behavioral deficits. The investigators found a direct relationship between the level of expression of the mutated gene, the number of neurofibrillary tangles, and the age of the mouse. This mouse model confirms the hypothesis that neuron loss can and does result from a mutation of the tau gene. 

APOE