ТОМ 4, СТ. 120 (стр. 285-287) // Апрель, 2003 г.
NEURONS, GLIA, AND PLASTICITY IN NORMAL BRAIN AGING
"Успехи геронтологии", 2002г., выпуск 10
© С.Е. Finch, 2002
г. Успехи геронтол. -2002.
-Вып. 10.-С, 35-39 УДК
Andrus Gerontology Center and Dept Biological Sciences, University of
Southern California, Los Angeles CA 90089, USA. E-mail: email@example.com
Early manifestations of brain aging have received much less attention than
the drastic degeneration of AD and MID. During nonpathological
changes of normal aging, brain systems differ in the involvement of
Spatial learning can become impaired without evidence for neuron loss,
whereas eye-blink conditioning deficits are well correlated with
Purkinje neuron loss. Glial activation, in particular the increased
expression of GFAP, may be a factor in impaired synaptic plasticity.
Lastly, I discuss how developmental variations in the numbers of
Purkinje cells and ovarian oocytes can be factors in outcomes of
aging that are not under strict genetic control.
Cognitive functions show many
alternative outcomes during aging. Individual trajectories range
from the devastating outcomes of Alzheimer disease (AD) and
multi-infarct dementia (MID) to very mild changes detected during
middle-age as well as at advanced ages that may not interfere with
most activities of daily living. Early indications of age
changes in brain functions are well documented during
middle-age in clinically healthy individuals, that is in humans aged
35-65 yrs and rodents aged 12-24 mos. These ages precede
the main phase of mortality accelerations which is a
characteristic of senescence in population [11,22]. For example,
psychologists have long recognized that the speed of processing
slows relatively early in aging in of adult humans and mammalian
models, as discussed at length in James Birren's classic monograph,
Psychology of Aging in 1964  and which anticipated a vigorous
research area of general importance to cognition in aging [17, 38].
Complex learning paradigms also show marked changes during middle
age, e.g. in Paul Bakes' novel paradigm of "Memorizing
2. Neuron numbers and functional brain aging
The cellular basis for most cognitive aging changes is not clear, but could in some learning
paradigms be independent of neuron loss. Neurons have long been
the main focus of study in brain aging because of the clear
importance of neuron loss to cognitive deficits in AD and MID.
However, certain brain aging changes do not involve neuron loss, as will be discussed below, and begin soon after maturation in the absence of
Mark West and colleagues have done a series of exacting studies of normal aging. Two year old
rats, which are equivalent to the human age group of 65, showed
marked individual differences in the extent of cognitive impairments
in a maze learning test The brains were examined in a subgroup
which was learning-impaired and a subgroup with learning which was
indistinguishable from young adults . Examination of hippocampal
neuron circuits by stereological techniques for precision counting
did not detect any neuron loss. The absence of neuron loss in the
zone of CA1 pyramidal neurons is particularly striking, because CA1
neurons are which heavily damaged in AD. Normal humans showed
similar stability of CA1 neuron number . Earlier reports of
extensive neuron loss during aging in the rodent hippocampus may be
due to stress exposure, in view of the correlations between
developmental stressors, the sensitivity of the adult
hypothalamic-pituitary-adrenal axis, and neuron loss during aging
[10, 26, 42].
On the other hand, impairments in eye-blink conditioning in normal aging may involve Purkinje
neuron loss in the cerebellum, in studies by Diana Woodruff - Pak.
Healthy human adults shows extensive differences in eye-blink
conditioning, a reflex pathway which is mediated by the Purkinje
cells of the cerebellum. A subgroup emerges during middle-age with
slower learning . At later ages, a subgroup of elderly with very
slow eye-blink conditioning subsequently became demented (probably
AD) [50, 53]. Rabbits, which do not develop Alzheimer-like changes
during aging, also show slowed eye-blink conditioned learning during
middle age . In this case, there is a strong correlation between
the numbers of Purkinje neurons and the efficacy of eye-blink
conditioning during aging, but also in young adults. There is
generally consistent evidence of Purkinje neuron loss during "normal
aging", which in humans is not apparent until after 60 [16, 53], but may begin in early middle-age in rodents by 12 months .
The difference between the cerebellum with its more pronounced
neuron loss versus the hippocampus with sporadic neuron loss is
consistent with the differential vulnerability of neurons to
ischemic injury and to AD.
Another important observation is
that young adults differ individually by up to 50% in the
numbers of Purkinje neurons, as shown directly by neuron counting in
rabbits and by MRI estimates of cerebellar volume in humans 
which both correlate with eye-blink conditioning. Moreover,
hippocampal neurons also show a 50% range of variations in rats [26,
35]. The origins of the variations and their possible significance
to outcomes of aging is discussed further below.
3. Glial activation during aging
dial changes of normal brain
aging have been largely neglected, because of the general assumption
that glial activation is secondary to neuron degeneration.
However, both astrocytes and microglia become activated early in
aging without concurrent diagnosable pathology. My lab is studying
the activation of astrocytes during normal aging, using glial
fibrillary acidic protein (GFAP) as a marker. GFAP expression
increases progressively during aging in humans and inbred lab
rodents, as measured by GFAP mRNA and protein [10, 15, 29,30, 32].
Although the cell volume of astrocytes compartment increases during
aging, the numbers of astrocytes shows much more modest changes
that are not detected in most studies of aging male rodents .
Rabbits also showed increased GFAP during aging . The similar
increases of GFAP in aging rodents and humans is important, because
inbred rodents do not develop Alzheimer changes of solid brain
amyloid deposits and hippocampal neurodegeneration unless
transfected with human AD genes.
The increased GFAP expression
during aging is due to increased transcription of GFAP, as shown by
in situ hybridization at a cellular level with intronic cRNA probes
[29, 30]. We have developed in vitro approaches to astro -cyte gene
expression changes during aging. Primary glia cultures from aging
adult cerebral cortex show the persistence of in vivo
activation, e.g. astrocytes from 12-mo vs 3 mo old rat cortex show
2-fold higher GFAP transcription when transfected with a full length
GFAP promoter . We hypothesize that GFAP transcription increases
during aging are caused by the increased load of oxidatively
damaged proteins, which occurs in tissues throughout the body
during aging, as well as in the brain [9, 10, 29, 41]. The level of
oxidative damage during aging is decreased by reducing average
caloric intake through "caloric restriction" paradigms
which robustly slow many aging processes inversely to the caloric
restriction over a 10-40% range in laboratory rodents [10, 41].
Caloric restriction also attenuates glial activation during aging, including GFAP
transcription, which we showed by in situ hybridization using GFAP
intron cRNA [29, 30]. Activation of the GFAP promoter by oxidative
stress (hydrogen peroxide, cysteamine)  may be mediated by a
functional NFkB-NF1 site in the upstream GFAP promoter [Wei, Morgan, Finch, in prep.], which is known to mediate responses
to oxidative stress in other genes. The GFAP promoter has highly
conserved domains in humans and rodents  which could mediate
certain shared (canonical) features of brain cell aging changes
shared in short- and long-lived mammals. The ensemble of oxidative
and inflammatory processes of aging throughout the body can be
considered as a "gero-inflammatory manifold", which may
underlie AD and many other age-related diseases [9, 10].
GFAP expression is usually
regarded as a secondary to neurodegeneration. However, we are
evaluating the possibility that the increased expression of
GFAP during aging may contribute to decreased synaptic functions. An
important clue comes from the wounding-in-a-dish model, in
which fetal neurons are cocultured with astrocytes [22, 25,37]. A
scratch wound causes immediate astrocyte reactivity. Neurite
outgrowth is greatly enhanced by treatment with antisense GFAP which
decreases astrocyte fibrosis and also reorganization of astrocytic
extracellular laminin [6, 21, 37]. Similarly, neurite outgrowth was
enhanced in astrocytes from the GFAP-KO genotype, which have lower
GFAP expression .
4. Sex steroids and sprouting
We are using the wounding-in-a
dish model analyze sex-steroid sensitive aspects of neuronal
sprouting and effects of aging. in vivo, we showed that the presence
of estradiol increases sprouting in the hippocampus after perforant
path lesions which are a model for hippocampal deafferentation
during AD [43, 44]. The sprouting responses depend on the presence
of apolipoprotein E (apoE), as shown by apoE knockout mice [43, 47].
Further, we are developing the hypothesis that sprouting also is
enhanced by estradiol through its inhibition of GFAP induction after
the lesion [37, 44]. In the wounding in a dish model, we showed that
GFAP transcription and protein are repressed by estradiol, in
association with increased sprouting and laminin reorganization
, just as obtained by antisense treatment [6, 22]. The effects
of E2 on GFAP transcription depend on a functional estrogen
response element in the upstream promoter  and interactions with
other loci in highly conserved regions of the GFAP promoter .
These findings support the hypothesis that the enhancement of
neuronal sprouting by E2 is driven by the repression of GFAP
transcription, which in turn decreases intermediate filament
formation with further downstream effects on laminin reorganization,
i.e. the inverse relationship in astrocytes between GFAP expression
and pro-neuritogenic laminin expression.
From the two paradigms of GFAP
decrease (E2-repression, antisense) which have the same effects on
laminin reorganization and neurite outgrowth, we propose that GFAP
expression is inverse to the pro-neuritogenic organization
of laminin in astrocytes. This hypothesis also predicts an
interaction with aging, because GFAP expression increases per
astrocyte during aging. The inverse GFAP-laminin hypothesis predicts
that the laminin reorganization in wounding responses should be
diminished in astrocytes derived from aging brains.
Responses to perforant path
lesions showed complex effects of aging in females: the induction of
neuronal sprouting was impaired in aging females and, unlike
young adults, was not sensitive to estradiol of ovariectomy. In
astrocytes, GFAP induction was greater than in young, whereas apoE
was diminished, which both could contribute to the impaired
sprouting . In view of the inverse association of astrocytic
GFAP expression with neuronal sprouting in the above culture model
and in many in vivo situations, we hypothesize that the increased
expression of GFAP in aging females is a factor in the impaired
sprouting. Preliminary results in the wounding-in-a-dish model show
that astrocytes from aging mice are not responsive to estradiol in
supporting neuron outgrowth, as observed in vivo.
I suggest further that there may
be general relationships between astrocyte hyperactivity during
aging and some neuronal functions which are modified by increased
astrocyte contact with neurons. In brief, several lines of evidence
indicate that astrocyte coverage of neurons can modifies synaptic
activity by controlling local neurotransmitter concentrations
[1, 33, 37]. It is possible that these mechanisms contribute to the
effects of 'glial scarring' from the astrocyte hypertrophy that has
long-been implicated in inhibiting neurite outgrowth in adult brain
We may then consider possible
interactions between glial activation and the concurrent changes
observed to begin soon after maturation in mild regressions of neuro
-transmitter binding sites in all mammals examined. One branch of
this large literature concerns various monoaminergic receptor
binding sites. We showed that decreases in certain monoamine binding
sites begin soon after maturation in cortical and subcortical
regions of normal humans and rodents, e.g. D2 binding dopaminergic
sites [20, 28, 40] The D2 site loss with normal aging was shown by
PET to parallel the postmortem findings across the adult life span
in several studies of normal humans [19, 46, 48]. PET studies of D2
sites in the rat also showed deficits in middle-age . The
functional significance of these age decreases in D2 binding sites
is indicated by age changes in drug sensitivity. For example,
quinpirol antagonism of cortical D2 sites which mediate delayed
recall becomes progressively more sensitive in aging monkeys 10, 20,
and 40 years . Moreover, glucose metabolism shows correlations
with the density of D2 sites measured by PET in normal humans,
which, again, shows a subgroup with lower values emerging during
middle-age . We may anticipate that age changes in
monoamine systems that influence multi-tasking and other executive
functions will become a major topic of research and pharmacologic
intervention. I suggest
the outline of a general hypothesis of brain aging, in which slowly
accumulating oxidative damage activates astrocytic transcription of
GFAP and other glial genes. The increased GFAP expression increases
astrocyte volume, which in turn expands the are of neuron
surfaces that are contacted by astrocyte membranes. Although it is
premature to discuss the many possible cellular consequences of
increased astrocyte-neuron contact, the experimental evidence
clearly shows effects of astrocyte coverage of neurons on
neurotransmitter functions [1, 33, 37].
5. Inidividual outcomes in aging and developmental variations in cell
Lastly, I briefly discuss the
issue of heritability in outcomes of brain aging, which can be
understood, I suggest, in terms of chance developmental variations
that influence brain cell numbers. This material draws from my
recent monograph co-authored with Tom Kirkwood: Chance, Development,
and Aging . An important example of nonheritable individual
variations in brain aging is given by identical (MZ) twins who show
major differences in the onset age of clinical dementia. In
Particular, Swedish MZ twins concordant for dementia differed by a
mean of 4.5 years; one concordant twin pair differed in dementia
onset by 16 years . Moreover, differences between MZ twins in
outcomes of cognitive aging are described for nondementing cognitive
changes: ".....idiosyncratic experience
[was] the environmental component that most determines individual
differences in cognitive abilities late in life" .
I suggest that differences in neuron numbers is another source of
individual variations within MZ twin pairs which would otherwise be
attributed to 'idiosyncratic experience'. Many cell populations
differ in numbers within identical genotypes due to developmental
variations . Data are strongest for neurons and for ovarian
oocytes which define at birth the reserves against which individuals
In young healthy adult rabbits,
the number of Purkinje neurons is implicated as the basis for
intersubject variability in learning curve for eye-blink
conditioning, with strong correlations of conditioning efficacy with
individual differences in Purkinje cell density that arose
during development . Young humans show similar correlations
of cerebellar volume with eye-blink conditioning , which
implicates variations in Purkinje in cell number. The Purkinje
system is the first clear example of developmental -ly-originating
differences in neuron number in a specific circuit in
neurologically normal adults that determine quantitative
variation of a brain function. As another example, MZ twin pairs
show substantial variation in the hippocampal volume [9, 34]
Variations in hippocampal neuron reserve between individuals could
be the basis for the co-MZ twin differences in the onset of clinical
impairments in memory.
Female reproductive aging also shows major differences between genetically
identical individuals which can be attributed to chance
developmental variations in the numbers of oocytes and
follicles as determined before birth. For example, inbred mice of
several strains show a >2-fold variability between individuals in
the numbers of oocytes and primary follicles in the ovary at birth,
which we hypothesize is the major factor in individual
variations of the age of oocyte depletion during middle-age . The
argument is based on an elegant experiment by my former students
James Nelson and Leda Felicio  that tested the relationship
between the numbers of oocytes present in the young ovary to the
time of later life reproductive senescence. This study
diminished the reserve oocyte pool in young adults by 'radical
ovarian resection' or surgical removal of most of the ovary. The
rate of loss of ovarian oocytes during postnatal aging approximates
zero-order kinetics, like radioactive decay, and can be fitted
nicely to the linear regression of log (oocytes) vs. age,
from which it can be calculated that a 90% reduction of oocyte loss
by surgical resection should cause the acceleration of reproductive
senescence by about 7 months. The results from longitudinal daily
observations of vaginal cytology confirmed this prediction for
both the age-related lengthening of cycles as well as the onset of
acyclicity. Thus, variations in the numbers of oocytes that arise
before birth in humans are a key factor in the age of natural
menopause five decades later. In turn, individual variations in the
age at menopause are risk factors of morbidity and mortality,
particularly osteoporosis with subsequent increased risks of
disabling fractures of bone and changes in blood lipids that
accelerate atherogenesis with increased risks of heart attacks and
strokes. In these conditions, estrogen replacement therapy
(ERT) shows generally consistent risk reduction. A recent addition
to the list of menopause-associated causes of mortality is the
possibility that the risk of AD in women can be reduced by ERT [18,
39]. An open question is how the age at menopause may interact with
the onset of AD. In view of the major effects of blood estradiol
levels on hippocampal synaptic efficacy and long-term potentiation
[3, 12], detailed investigations are needed of relationships between
the duration of estrogen deficiencies after menopause and cognitive
changes. These questions may extend to males, in view of
associations of cognitive performance and plasma estradiol 
and the efficacy of estradiol on long-term potentiation in
young adult male rat hippocampal slices .
This work was supported by grants to the author from the National
Institute on Aging (AG 09793, AG-13499; AG-14571),
the Alzheimer's Association, and the John Douglas French Foundation
for Alzheimer disease.
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