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Neurobiotogy of Aging, Vol. 15. Suppl. 2, pp. $85-$86, 1994
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Tau Protein and Alzheimer's Disease
EVA-MARIA MANDELKOW AND ECKHARD MANDELKOW
Max-Planck-Gesellschaft Research Institute, Structural and Molecular Biology, Narkestrasse 85, D-22603,
Hamburg, Germany
1. It is aggregated into paired helical filaments (PHF) which coalesce into neurofibrillary tangles. These can be visualized and
localized postmortem by special staining techniques.
2. Tau in AD is modified in several ways, e.g., by phosphorylation, proteolysis, and ubiquitination. Abnormal phosphorylation is probably the first and most critical modification; the
other two modifications are likely to be secondary reactions by
the body's defense system.
3. Abnormal tau spreads in a highly characteristic spatial and
temporal sequence, starting in select neurons of the transentorhinal region. This provides the basis of subdividing the disease into 6 stages, of which only the late stages of 5 and 6 meet
the clinical diagnosis of AD unambiguously (for review see
ref. 2).
ALZHEIMER'S Disease (AD) is a slow disease, specific for human brain, of unknown origin and not curable thus far. This review defines some of the boundary conditions of research.
Because AD is slow, its early stages are not noticed clinically.
This hampers the development of drugs that might slow down or
reverse the progression of the disease. Conversely, when the disease is noticed clinically, much of the brain damage is irreversible.
Because AD is restricted to human brain, it is not accessible to
most methods of experimental analysis.
Because the origin of AD is unknown, it is difficult to search
for diagnostic tools or for a medication.
The known correlations with genetic or environmental factors
are, in most cases, not strong enough to determine a unique chain
of cause and effect. This illustrates the need for the following: (a)
Model systems easily accessible to experimentation and analysis,
such as cell models or animal models (e.g., transgenic animals);
(b) Assays for early detection, possibly from CSF, from sources
other than brain (blood, biopsies from other tissues), or methods
such as brain imaging (PET, MRI, etc.).
If experimental systems and early detection methods were
available, it would be possible to search for treatment even before
the origins of AD are known. However, ultimately, the origins
will have to be found on the basis of cells or molecules to allow a
rational diagnosis, prevention, or treatment.
At present, the search is restricted to a few markers that are
thought to be characteristic of AD. This includes genetic linkages
(implying proteins, e.g., APP or APOE), or morphological markers (abnormal aggregates implying proteins, e.g., APP or tau). It
is possible that these proteins are not at the root of the disease, but
a promising avenue of research is to use these markers as a "semaphore" to detect underlying abnormal events. The combined use
of biochemical, cell biological, and molecular biological approaches has yielded several interesting results. In the case of
APP, they point to abnormal proteolytic cleavage and/or accumulation of the protein that causes the fragments (A[3) to aggregate.
In the case of tau, they point to abnormal phosphorylation and an
imbalance in signal transduction cascades, also with the result of
abnormal aggregation.
These observations prompt the following questions: (a) What
causes the selective degeneration of certain neurons, especially at
the early stages? What makes these neurons special in terms of
function, differentiation, activity? Alternatively, are these neurons
selectively exposed to some toxic factors (glutamate, AI3, other
stress-inducing substances)? Are these neurons particularly vulnerable? (b) Of all proteins in a cell, why is it that tau reacts in a
pathological fashion? Or are there other proteins that become abo
normal but are not visible by pathological aggregation? What
causes tau to aggregate? Why does aggregation take place in selected regions of a cell? Why does abnormal tau become hyperphosphorylated? Because tau's function is linked to microtubules,
are any of the microtubule-based processes impaired (e.g., intracellular traffic, neurite extension)? (c) What causes the spreading
of the neurofibrillary changes in a reproducible fashion? Is there a
gradient of toxic effects, a gradient of vulnerability? Or do affected cells communicate their degeneration to others? Do the
body's defense mechanisms slow down or speed up the spreading?
The first two sets of questions call for a cell biological approach. If one could create cell models that mimick the behavior
of the degenerating neurons one could assay for toxic substances
or special properties. The cell models could be of neuronal origin
or other cultured cells that are engineered to show "Alzheimerlike" behavior. Such engineering would involve, for example, the
transfection with genes coding for tau protein, APP, ApoE receptors, or other proteins suspected to be involved (kinases, phosphatases). A number of labs are working on these issues and
interesting results are beginning to emerge. The third set of questions is probably the most difficult to answer because they deal
with whole brain tissue with a heterogeneous composition. These
questions could possibly be addressed with suitable animal models, but even if they were available, the results are likely to be
complex.
For the moment, the cell biological approach combined with
the methods of biochemistry and molecular biology, seems to be
TAU PROTEIN
The following discussion is restricted to tau protein. Tau is one
of the microtubules associated proteins that are thought to have a
role in the stabilization of neuronal microtubules; these in turn
provide the tracks for intracellular transport. Tau appears to be one
of the earliest markers of AD and forms the neurofibrillary
changes (neuropil threads, neurofibrillary tangles, neuritic
plaques). Tau protein in AD is distinct from normal brain in several ways:
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MANDELKOW AND MANDELKOW
the most promising one for studying the etiology of AD. Even
though the origins are unknown one can take the attitude that
pathological tau may serve as a pointer for searching in the right
direction. In this regard, several important advances have been
made in recent years (for recent reviews, 6,9,4,10).
Tau has been identified as the primary component of abnormal
neurofibrillary aggregates. Many of the normal and abnormal
phosphorylation sites have been mapped, in particular, certain
serine-proline or threonine-proline motifs because their phosphorylation leads to an Alzheimer-like antibody reactivity (8). Several
protein kinases that are able to phosphorylate these motifs have
been identified, including MAP kinase, GSK-3, cdk5, and others
(3). In addition, there are other kinases that can detach tau from its
natural partner, microtubules; at least one of the sites (serine 262)
is also characteristic of AD tau (5). The "abnormal" phosphorylation sites can be cleared again by certain phosphatases (calcineurin, PP-2A; ref. 3a). Some of the sites are transiently phosphorylated in foetal brain, suggesting that the degenerating neuron
reacts to some stimulus in a fashion reminiscent of the fetal stage
(7). Finally, the aggregation of tau into PHFs can be reconstructed
in vitro (11).
The results on tau's phosphorylation all point to an imbalance
in the signal transduction pathways involving cascades of phosphorylation and dephosphorylation. In this sense, tau has already
fulfilled one role as a semaphore. It has revealed a potential link of
the AD pathology to a general principle governing cell regulation.
The field of signal transduction is complex, but it is evolving very
rapidly. Because of its fundamental importance one can expect
that it will serve as a guide for experiments in the field of AD
research (as well as other disease states). For example, it is now
possible to put a cell under stress such that the cell responds by
activating certain kinases which could phosphorylate tau protein in
a "pathological" fashion--this is the beginning of a cellular
model system.
SUMMARY
The etiology of Mzheimer's disease is still unknown. Because
the disease is specific for human brain, a rational search for early
diagnosis or prevention is very difficult. This calls for the development of cellular models that mimick the degeneration of neurons
in AD. The brains of AD patients contain markers whose composition and location is characteristic of the disease; one of the most
reliable markers is tau protein in its pathologically phosphorylated
and aggregated form. This form of tau can serve as a guide to the
origins of the pathology. One goal of research that should be
feasible within the near future is to construct a cell that induces the
same abnormal changes in tau protein in response to defined stimuli (extracellular signals, toxins, stress, etc.). This model can then
be used to identify possible substances that might cause the disease, or identify strategies for preventing it. Once they are defined
on a cellular level, the next step would be to test them on (transgenic) animal models which are being developed at present.
REFERENCES
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2. Braak, H.; Braak, E. Pathology of Alzheimer's disease. In: D. Calne
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Biernat, J.; Gods, J.; Doree, M.; Mandelkow, E. Mitogen-activated
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Alzheimer paired helical filaments by calcineurin and phosphatase2A. FEBS Lett. 336:425-432; 1993.
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