Alzheimer's Disease: A two-hit wonder?
Authors: Miller Katharine 
Published: August 2003

The accumulation of senile plaques and neurofibrillary tangles in the brain marks the onset of Alzheimer's Disease (AD) (see
"Detangling Alzheimer's Disease"
). But researchers aren't sure what causes plaques and tangles to form. One theory posits two possible upstream sources: oxidative stress and an aberrant message that tells neurons to divide. New results suggest that this duo hits AD victims well before signs of the disease arise. And the double whammy appears to correlate with the onset of cellular pathology. Only neurons that take both an oxidative blow and a cell-splitting jolt develop classic signs of AD, the researchers propose. If the results hold up, they'll provide new targets for AD prevention and treatment.

Addition of a phosphate group to a protein called tau can spur tangle formation, and molecules that perform this reaction--at least in the test tube--have drawn researchers' attention as possible triggers for AD. Two such proteins, c-Jun N-terminal kinase (JNK/SAPK) and extracellular signal-regulated kinase (ERK) appear in the diseased neurons of people with Alzheimer's disease. Two different stimuli--both known to occur in AD-afflicted brains--activate these proteins. Oxidative stress (see
"The Two Faces of Oxygen"
) riles JNK/SAPK, and a message for the cell to divide pushes ERK's buttons. Until now, however, no one knew whether the two messages zing tau at the same time or in a specific order.

To better understand the connection between oxidative stress, the signal to divide, and the appearance of cellular signs of disease, Zhu and colleagues examined the chronological relation between the appearance of JNK/SAPK and ERK, tau tangles, senile plaques, and other indicators of AD. They examined brain specimens from seven controls age 17 to 81 and 17 people age 60 to 91 with limited, mild, or severe AD. Some neurons in people with no signs of the disease display ERK or JNK/SAPK alone, but never in combination--and the proteins reside in the nucleus, where they don't encounter tau. In contrast, individuals who barely exhibited mental failings and those who suffered from mild cases of AD display both ERK and JNK/SAPK in some neurons; the proteins appear in the cytoplasm, where they can spark tangle formation. These people also have small numbers of tangles in their brains. In the most severe cases of AD, the JNK/SAPK and ERK duo associates exclusively with cells that show pathological signs of AD.
Because the study showed that either protein can crop up first in the AD-susceptible parts of the brain and that both proteins eventually arise in people stricken with the disease, the results suggest a two-hit model of Alzheimer's disease: Either a signal to divide or oxidative stress instigates the pathological process, but both are required to complete the task. The finding raises the possibility that each of these events lays the groundwork for the other. If so, confining the damage to one hit may help us keep our wits intact.
--Katharine Miller; suggested by Amir Akha

X. Zhu, R. Castellani, A. Takeda, A. Nunomura, C. Atwood, G. Perry, M. A. Smith, Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: the 'two-hit' hypothesis.
Mech. of Ageing and Dev.
123
, 39-46 (2001).
[Abstract]
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