Here's the other half I promised so ya'll can put them together! Wendy
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Historically, diseases have been named and classified by their clinical
symptoms and characteristic pathology. If there is one dramatic consequence
of the molecular genetic revolution on contemporary studies of disease, it
is the extreme variations in phenotype that can come from similar genetic
lesions. Perhaps the most striking examples to date are the divergent
phenotypes that result from nearly identical PRPP178 mutations. This mutant
prion gene can cause either CJD or fatal familial insomnia (FFI), two
distinctly different fatal phenotypes21,36. It appears that a small change
in DNA sequence--a polymorphism at codon 129--dictates the phenotype.
(Although the prion protein can aggregate and form amyloid plaques, neither
PRPP178 disease, CJD, or FFI is characterized by prominent plaque
formation.)
Another example of similar genotypes and diverse phenotypes is DRPLA22-24.
A triplet-repeat variation in the same gene causes one set of disease
symptoms in the Japanese cases, which are clinically distinct from the
disease manifestations in African Americans, again pointing to the large
phenotypic effects of small variations in the genetic background.
My view of the future for the study of AD is that, by understanding how
different isoforms of ApoE participate in neuronal metabolism and the
mechanisms of pathogenesis that lead to the synaptic and neuronal loss
characteristic of AD, we can decipher other principles of cerebral
pathology and processes that are currently undefined14-16,20-24,37.
ApoE may be the "vitamin C" of neurons.
As stated above, ApoE is present in neurons of patients with late-onset AD
and in age-matched controls who do not have AD19,34 (see figure 3).
Although ApoE is made in large quantities outside the CNS, where it
contributes to bulk lipid metabolism, the quantity of ApoE that is present
in brain neurons is infinitesimal compared with the quantity in glial
cells19,38,39.
ApoE appears not to be made in neurons, but neurons probably acquire the
protein from astrocytes and require its presence. There must be a currently
undefined, neuron-specific mechanism that allows small amounts of
ApoE--once it is inside a neuron--to escape the intraneuronal endosomal
compartment and enter the cytoplasm. APOE-deficient knockout mice develop
early and severe abnormalities in the morphology of their cortical-neuron
dendrites, presumably as a consequence of having no ApoE in their brains40.
Thus, ApoE is similar to a vitamin, such as vitamin C, in human physiology:
The neuron does not make it but it is necessary for good health.
Our recent studies suggest that the ApoE3 and ApoE2 isoforms may lead to
better brain function over time than ApoE4. Studies of fraternal twins have
revealed lower cognitive performance in normal (non-AD) older adult male
twins who carry the APOE4 allele41. Also, a person's ability to recover
neuropsychological functions after stress, such as cardiopulmonary bypass
surgery, has been related to the presence or absence of an APOE4 allele42.
The neurobiology and hereditary factors that underlie neuropsychological
functioning and responses to environmental stress are only beginning to be
appreciated and studied. The normal metabolic role of small quantities of
cytoplasmic ApoE in neurons and the pathways for regulating the neuronal
intake of ApoE may provide new clues to the study of normal brain function
and response to metabolic stresses5,42.
ApoE seems to function as a neuronal metabolic co-factor for microtubular
maintenance and repair and, possibly, for other physiologic functions, and
it may play akey role in the selective vulnerability that characterizes
some neurodegenerative diseases. The intriguing localization of ApoE to
peroxisomes may suggest that oxygen metabolism is altered in several major
neurodegenerative diseases, including amyotrophic lateral sclerosis,
Parkinson's disease, and the collection of disorders that resemble AD but
that involve different brain pathologies17,43.
It is natural that the impetus for these basic studies should come from
scientists who are interested in the nature of diseases and the
possibilities for treatment. The studies of genes that increase
susceptibility to disease will need to be verified by epidemiological
studies controlled for age, sex, race, and ethnic variables. The
association of the APOE4 allele with more rapid progression to late-onset
AD is a wonderful example of how a previously known genetic variation that
can increase the susceptibility to fatal myocardial infarctions can be
extended to another age-dependent disease44. To understand the epidemiology
of diseases in different populations with variable frequencies of the APOE
alleles, we must focus our attention on the effects of genetic variations
as well as of interactions with diet, exercise habits, education, and other
environmental factors on the rate of disease expression.
Crystal balls do not provide as much light as do data from experiments.
Although this commentary may sound speculative, there is nothing more
conjectural than being asked to write about the future. I think basic
neurobiologists will lead the way in determining the role of ApoE in
neurons and that this information will feed back to investigators who are
interested in brain diseases. The ApoE-isoform-specific metabolism that
leads to AD will be defined and targeted for pharmacologic therapy. As a
"long-shot" bet, many of my colleagues in AD research who are firmly
engrossed in studying the role of A-beta in AD may come to understand that
an individual's genotype explains his or her phenotype, not that phenotype
predicts mechanisms of pathogenesis. The concept of several "Alzheimer's
diseases" will become more apparent; whether and how they are interrelated
will be tested45. Being somewhat of agambler, my "surest bet" is that new
concepts of basic science of the brain will emerge from controversial data
that cannot now be explained by prevailing hypotheses.
If AD is a universal corollary of long life with variations in APOE
genotype being responsible for the proportion of individuals who will
develop AD during their life span, then nothing needs to be replaced by
gene therapy. Indeed, we need to enhance or inhibit by 10-15 percent the
rate of relevant critical reactions to push the curve of age of AD onset to
the right. If genotype does predict phenotype, then we must describe the
genetically relevant mechanisms that are specifically affected by different
ApoE isoforms--and then determine how to slow the processes down. The AD
drugs of the future will target genetically relevant processes, rather than
the phenotypic consequences of the disease.
Acknowledgment
Without the far-sighted thinking of Dr. Zavin Khachaturian and the National
Institute on Aging (NIA), the support for the discovery of APOE as a
susceptibility locus for Alzheimer's disease would not have occurred. NIA
funding of the Joseph and Kathleen Bryan Alzheimer's Disease Research
Center and the Leadership and Excellence in Alzheimer's Disease (LEAD)
Award provided most of the financial support. The critical element of the
LEAD Award--not having to undergo competitive review for seven
years--provided an opportunity to go in new directions, rather than pursue
safe renewals.
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*Alzheimer's Disease Research Center, Bryan Research Building, Room 227,
Duke University Medical Center, Durham, NC 27710-2900. Comments intended
for publication should be addressed to Advice and Dissent, The Journal Of
NIH Research, 1444 I St., N.W., Suite 1000, Washington, DC 20005.
Allen D. Roses is the Jefferson Pilot Professor of Neurobiology and
Neurology in the Departments of Medicine and Neurobiology, Bryan
Alzheimer's Disease Research Center, Duke University Medical Center,
Durham, N.C.
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