Neuroprotective and neurorestorative signal transduction mechanisms in brain aging: modification by genes, diet and behavior.

Abstract

Cells in the brain deploy multiple mechanisms to maintain the integrity of nerve cell circuits, and to facilitate responses to environmental demands and promote recovery of function after injury. The mechanisms include production of neurotrophic factors and cytokines, expression of various cell survival-promoting proteins (e.g. protein chaperones, antioxidant enzymes, Bcl-2 and inhibitor of apoptosis proteins), protection of the genome by telomerase and DNA repair proteins, and mobilization of neural stem cells to replace damaged neurons and glia. The aging process challenges such neuroprotective and neurorestorative mechanisms, often with devastating consequences as in Alzheimer's disease (AD), Parkinson's and Huntington's diseases and stroke. Genetic and environmental factors superimposed upon the aging process can determine whether brain aging is successful or unsuccessful. Mutations in genes that cause inherited forms of AD (amyloid precursor protein (APP) and presenilins), Parkinson's disease (alpha-synuclein and parkin) and trinucleotide repeat disorders (e.g. huntingtin and the androgen receptor) overwhelm endogenous neuroprotective mechanisms. On the other hand, neuroprotective mechanisms can be bolstered by dietary (caloric restriction, and folate and antioxidant supplementation) and behavioral (cognitive and physical activities) modifications. At the cellular and molecular levels, successful brain aging can be facilitated by activating a hormesis response to which neurons respond by upregulating the expression of neurotrophic factors and stress proteins. Neural stem cells that reside in the adult brain are also responsive to environmental demands, and appear capable of replacing lost or dysfunctional neurons and glial cells, perhaps even in the aging brain. The recent application of modem methods of molecular and cellular biology to the problem of brain aging is revealing a remarkable capacity within brain cells for adaptation to aging and resistance to disease.

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Neurobiology of Aging 23 (2002) 695–705
Neuroprotective and neurorestorative signal transduction mechanisms
in brain aging: modification by genes, diet and behavior
Mark P. Mattsona,b,∗, Wenzhen Duana, Sic L. Chana, Aiwu Chenga, Norman Haugheya,
Devin S. Garya, Zhihong Guoa, Jaewon Leea, Katsutoshi Furukawaa
aLaboratory of Neurosciences, National Institute on Aging Gerontology Research Center 4F01,
5600 Nathan Shock Drive, Baltimore, MD 21224, USA
bDepartment of Neuroscience, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205, USA
Received 11 July 2001; received in revised form 14 December 2001; accepted 26 December 2001
Abstract
Cells in the brain deploy multiple mechanisms to maintain the integrity of nerve cell circuits, and to facilitate responses to environmental
demands and promote recovery of function after injury. The mechanisms include production of neurotrophic factors and cytokines,
expression of various cell survival-promoting proteins (e.g. protein chaperones, antioxidant enzymes, Bcl-2 and inhibitor of apoptosis
proteins), protection of the genome by telomerase and DNA repair proteins, and mobilization of neural stem cells to replace damaged
neuronsandglia.Theagingprocesschallengessuchneuroprotectiveandneurorestorativemechanisms,oftenwithdevastatingconsequences
as in Alzheimer’s disease (AD), Parkinson’s and Huntington’s diseases and stroke. Genetic and environmental factors superimposed upon
the aging process can determine whether brain aging is successful or unsuccessful. Mutations in genes that cause inherited forms of
AD (amyloid precursor protein (APP) and presenilins), Parkinson’s disease (?-synuclein and parkin) and trinucleotide repeat disorders
(e.g. huntingtin and the androgen receptor) overwhelm endogenous neuroprotective mechanisms. On the other hand, neuroprotective
mechanisms can be bolstered by dietary (caloric restriction, and folate and antioxidant supplementation) and behavioral (cognitive and
physical activities) modifications. At the cellular and molecular levels, successful brain aging can be facilitated by activating a hormesis
response to which neurons respond by upregulating the expression of neurotrophic factors and stress proteins. Neural stem cells that reside
in the adult brain are also responsive to environmental demands, and appear capable of replacing lost or dysfunctional neurons and glial
cells, perhaps even in the aging brain. The recent application of modem methods of molecular and cellular biology to the problem of brain
aging is revealing a remarkable capacity within brain cells for adaptation to aging and resistance to disease.
© 2002 Elsevier Science Inc. All rights reserved.
Keywords: Alzheimer’s disease; Apolipoprotein; Apoptosis; BDNF; Caloric restriction; Chaperone; Folic acid; Parkinson’s disease; Telomerase
1. Introduction
Many persons live for nine or more decades and enjoy a
well-functioning brain until the very end of life. We there-
fore know what the brain is capable of and, accordingly, a
major goal of research in the area of the neurobiology of ag-
ing should be to identify ways to facilitate successful brain
aging in everyone. Studies of brains of the oldest old have
provided evidence for stability as well as plasticity in suc-
cessful brain aging. In many brain regions there is very little
or no decrease in numbers of neurons, while in some brain
regions neuronal loss may occur [67]. Nerve cell loss during
aging may be compensated by expansion of dendritic arbors
and increased synaptogenesis in the remaining neurons [4].
∗Corresponding author. Tel.: +1-410-558-8463; fax: +1-410-558-8465.
E-mail address: mattsonm@grc.nia.nih.gov (M.P. Mattson).
In addition, it is thought that many neurons remain in the
brain for a lifetime, although in some brain regions such as
the olfactory bulb and dentate gyrus of the hippocampus,
there is clearly a continual replacement of neurons from a
pool of progenitor (stem) cells [30,101]. This regenerative
capacity of brain may persist throughout the life-span.
While the brain can age successfully, its cells may face
considerable adversity during the journey (Fig. 1). Increased
oxidative stress (oxyradical production) and accumulation of
oxidatively damaged molecules (proteins, nucleic acids and
lipids) promote dysfunction of various metabolic and sig-
naling pathways [62]. Neurons may also face energy deficits
as the result of alterations in the cerebral vasculature and
in mitochondrial function [42]. General, as well as specific,
mechanisms of cellular signal transduction are altered dur-
ing brain aging. Examples of widely used signaling mech-
anisms affected by aging include protein phosphorylation
0197-4580/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved.
PII: S0197-4580(02)00025-8

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M.P. Mattson et al./Neurobiology of Aging 23 (2002) 695–705
Fig. 1. With advancing age there is a progressive accumulation of dam-
aged molecules and impaired energy metabolism in brain cells. In suc-
cessful brain aging, the neurons and glial cells adapt to the adversities of
aging by increasing their ability to cope with stress, and by compensating
for lost or damaged cells by producing new brain cells and remodeling
neuronal circuits (hormesis and adaptation). In unsuccessful aging, molec-
ular damage to neurons and inflammatory processes result in synaptic
dysfunction and neuronal degeneration and death, without replacement of
the lost neurons.
(alterations in kinases and phosphatases) [50], cellular cal-
cium homeostasis [77], protein folding and proteolysis [61],
and gene transcription [64]. Among neurotransmitter sys-
tems, dopaminergic signaling appears to be consistently al-
tered during aging with a progressive decrease in signaling
via the D2 subtype of receptor [104]. These kinds of alter-
ations that occur during normal aging likely set the stage for
catastrophic neurodegenerative disorders that may be trig-
gered by particular genetic predispositions or environmental
factors.
Studies of embryonic and early postnatal development,
and of synaptic plasticity in the young adult, have made
a major contribution to our current understanding of the
molecular and cellular mechanisms that determine whether
brain aging occurs successfully or manifests dysfunction
or disease. This is because the same intercellular signals
and intracellular transduction pathways that regulate neurite
outgrowth, synaptogenesis and cell survival during devel-
opment are also operative throughout life. Although new
signaling systems continue to be discovered, several classes
of signaling molecules have emerged with neurotrophic
factors, neurotransmitters, cytokines and steroids being
particularly important in brain aging. Neurotrophic factors
such as neurotrophins (brain-derived neurotrophic factor
(BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3)
and neurotrophin-4 (NT-4)), fibroblast growth factors, glial
cell line-derived neurotrophic factor (GDNF) and ciliary
neurotrophic factor (CNTF) have been shown to promote
the survival of specific populations of brain neurons under
experimental conditions relevant to brain aging and neu-
rodegenerative disorders [81]. In addition to their roles as
mediators of synaptic transmission, neurotransmitters such
as glutamate, acetylcholine and dopamine also play impor-
tant roles in regulating the formation of neuronal circuits
during development and in influencing the neurodegenera-
tive process in brain disorders of aging [77]. The status of
such neurotransmitter, trophic factor and cytokine signaling
systems is likely to have a major influence the outcome of
brain aging.
2. Hazards encountered by cells in the aging brain
and their possible consequences
As is the case in other organ systems, cells in the brain
encounter a cumulative burden of oxidative and metabolic
stress that may be a universal feature of the aging pro-
cess. Fingerprints of increased oxidative stress during
brain aging can be found on each of the major classes of
cellular molecules including proteins, nucleic acids and
lipids (Fig. 1). Oxidative modifications of proteins docu-
mented in neurons during aging include carbonyl forma-
tion [10,12,21], covalent modification of cysteine, lysine
and histidine residues by the lipid peroxidation product
4-hydroxynonenal [98], nitration of proteins on tyrosine
residues [110] and glycation [96]. A common oxidative
modification of DNA observed during brain aging is the for-
mation of 8-hydroxydeoxyguanosine [111]. Increased lipid
peroxidation during brain aging is manifest in the accumu-
lation of lipid peroxidation products in neurons [83]. Each
of the modifications of proteins, nucleic acids and lipids
just described are greatly exacerbated in neurodegenerative
disorders such as AD and Parkinson’s disease, consistent
with a major role for oxidative stress of aging in the patho-
genesis of those disorders [76]. Analyses of experimental
animal and cell culture models of age-related neurodegen-
erative disorders such as AD and Parkinson’s disease and
stroke have provided insight into the mechanisms that re-
sult in increased oxidative stress and damage to proteins,
nucleic acids and membrane lipids. In Alzheimer’s disease
(AD), altered proteolytic processing of the ?-amyloid pre-
cursor protein (APP) results in increased production of a
long (42 amino acid) form of amyloid ?-peptide which has
a propensity to self-aggregate and form insoluble plaques in
the brain [79]. During the process of aggregation, amyloid
?-peptide generates reactive oxygen species that can induce
membrane lipid peroxidation. The lipid peroxidation results
in impairment of the function of membrane ion transport
and glucose transport proteins which, in turn, leads to a dis-
ruption of neuronal ion homeostasis and energy metabolism
[79]. These actions of amyloid ?-peptide can cause dys-
function of synapses and can trigger a cell death cascade
called apoptosis [23,85]. Degeneration of dopaminergic
neurons in the substantia nigra and striatum of Parkinson’s
patients may be triggered by mitochondrial impairment

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M.P. Mattson et al./Neurobiology of Aging 23 (2002) 695–705
697
and increased oxidative stress resulting from aging and ex-
acerbated by environmental toxins such as pesticides and
iron [48]. In the most common late-onset form of AD and
Parkinson’s disease the neurodegenerative cascade is most
likely promoted by environmental factors (see section on
environmental factors) that result in increased oxidative and
metabolic stress. However, there are more rare inherited
forms of these diseases in which disease onset occurs at an
early age (30–60 years of age); a few of the genetic defects
have been identified including mutations in APP and prese-
nilins that cause AD [36,79], and mutations in ?-synuclein
and parkin that cause Parkinson’s disease [55,100].
Although some oxidative modifications of molecules in
cells may serve adaptive signaling roles (e.g. S-nitrosylation
of proteins; [41]), most such modifications impair the func-
tion of the modified molecule and can trigger cell death
cascades. Studies of patients and experimental models of
neurodegenerative disorders have revealed several specific
examples of oxyradical-mediated dysfunction of regulatory
proteins in neurons and glial cells. The membrane lipid
peroxidation associated with amyloid deposition in AD re-
sults in impairment of the function of the plasma membrane
Na+/K+- and Ca2+-ATPases [73,74], the neuronal glucose
transporter GLUT3 [75], the astrocyte glutamate transporter
EAA1 [52]. The coupling of neurotransmitter receptors to
GTP-binding proteins, including muscarinic acetylcholine
receptors and metabotropic glutamate receptors, is impaired
by oxidative stress [7,53]. Oxidative modification of DNA
can result in single- and double-strand breaks which, un-
der conditions of an inadequate DNA repair response, can
trigger an apoptotic cell death program involving the tumor
suppressor protein p53, pro-apoptotic Bcl-2 family mem-
bers such as Bax, and one or more cysteine proteases of the
caspase family [95].
3. Genetic and environmental factors in brain
aging and neurodegenerative disorders
An increasing number of genetic and environmental fac-
tors are being identified that can render neurons vulnerable
to the aging process. An understanding of how such causal
or predisposing risk factors promote neuronal dysfunction
and/or death is critical for developing approaches to pre-
servefunctionalneuronalcircuits.Wewillthereforedescribe
several prominent genetic aberrancies and environmental
factors that either cause or increase risk of specific neurode-
generative disorders of aging. AD can be caused by mu-
tations in the genes encoding the APP, presenilin-1 or -2.
Each of these mutations results in an increased production
of amyloid ?-peptide. Interestingly, the APP and presenilin
mutations also decrease levels of a secreted form of APP that
has been shown to promote synaptic plasticity (learning and
memory) and survival of neurons [29,46]. At the heart of
the mechanism whereby the APP and presenilin mutations
promote synaptic dysfunction and neuronal degeneration is
perturbed cellular calcium homeostasis [36,79,85]. In the
case of APP mutations, the alterations in calcium home-
ostasis are the consequence of increased amyloid ?-peptide
production and decreased secreted APP production [79]. In
the case of presenilin mutations, a primary defect in endo-
plasmic reticulum calcium regulation has been established
[36,85]. The mutant presenilin-1 protein acquires an adverse
property that results in an overfilling of endoplasmic reticu-
lum calcium stores and an abnormality in capacitive calcium
entry.
Abnormalities in synaptic transmission may be a major
consequence of mutations in the ?-synuclein gene that cause
familial Parkinson’s disease. Mice lacking ?-synuclein ex-
hibit a reduction in striatal dopamine levels, an attenuation
of the locomotor response to amphetamine, and enhanced
dopamine release from nigrostriatal terminals upon paired
stimuli suggesting that ?-synuclein is an activity-dependent
regulator of dopamine release [1]. It remains to be estab-
lished if ?-synuclein mutations that cause Parkinson’s dis-
ease result in similar abnormalities in dopaminergic neuro-
transmission, or if they result from a gain-of-function of the
mutant protein. Huntington’s disease is an age-related neu-
rodegenerative disorder caused by trinucleotide expansions
of the huntingtin gene resulting in a huntingtin protein with
long stretches of polyglutamine repeats. Studies of trans-
genic mice and cultured neurons expressing mutant hunt-
ingtin suggest that the mutant protein may form abnormal
aggregates, promote mitochondrial dysfunction and activate
apoptotic biochemical cascades involving caspases [116].
Genetic factors that specifically increase risk of stroke are
not well understood, whereas genes involved in lipoprotein
metabolism that affect risk of cardiovascular disease simi-
larly affect risk of stroke. However, the discovery that mu-
tations in Notch-3 can cause a syndrome characterized by
strokes is providing new insight into signaling pathways that
influence cerebrovascular health during aging [51].
Genetic factors that increase risk of age-related neurode-
generative disorders are also being discovered, with one
prominent example being apolipoprotein E polymorphisms.
There are three isoforms of apolipoprotein E [2–4]; individ-
uals that inherit the E4 allele are at increased risk of AD.
Although the molecular basis for this effect of apolipopro-
tein E genotype remains to be fully understood, experi-
mental findings suggest that the E2 and E3 isoforms ex-
hibit an antioxidant activity not possessed by the E4 iso-
form [99]. Other genetic polymorphisms have been reported
to affect risk of AD including those in the genes encoding
alpha2-macroglobulin, an apolipoprotein receptor and an-
giotensin converting enzyme. However, in the latter three
cases many other studies have not confirmed the associ-
ations [102]. Numerous reports of associations of genetic
polymorphisms with Parkinson’s disease have appeared in-
cluding those in the genes encoding cytochrome p450 en-
zymes, N-acetyltransferase 2, monoamine oxidase-B and
glutathione transferase; some of these remain viable candi-
dates [13,114]. Additional genetic predisposition factors for

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M.P. Mattson et al./Neurobiology of Aging 23 (2002) 695–705
these and other age-related neurodegenerative disorders will
surely be identified.
Theidentificationofgenemutationsthatcauseage-related
neurodegenerative disorders has led to the development
of animal and cell culture models that have allowed rapid
progress in understanding the cellular and molecular cas-
cades responsible for neuronal degeneration and to novel
preventative and therapeutic strategies. For example, the
phenotypes of APP mutant mice and presenilin mutant
mice provide strong evidence that these mutations result
in altered APP processing and perturbed cellular calcium
homeostasis, respectively [31,36]. An excellent model of
amyotrophic lateral sclerosis (ALS) resulted from the iden-
tification of mutations in the Cu/Zn-SOD gene as causing
familial ALS. Transgenic mice expressing mutant human
Cu/Zn-SOD exhibit a phenotype remarkably similar to hu-
man patients, and these mice are now routinely being used
to screen compounds to determine their ability to delay
disease onset and/or progression [70].
Other studies have identified environmental factors that
can increase risk of one or more neurodegenerative disor-
ders. Epidemiological studies have provided evidence that
individuals with a higher level of education are at reduced
risk for AD [24]. Studies of dietary links to Parkinson’s
disease and AD suggest that individuals with a low calorie
intake are at reduced risk [66,91], while those with a low
level of folic acid in their diets are at increased risk [15,60].
Head trauma may also increase risk of AD and Parkinson’s
disease [71,119]. Exposure to environmental toxins such as
the pesticide rotenone may increase risk of Parkinson’s dis-
ease [5]. Similar to atherosclerotic heart disease, overeat-
ing, a high fat diet, smoking, folic acid deficiency and a
sedentary lifestyle are risk factors for stroke [22]. Studies in
animals models of AD and Parkinson’s disease and stroke
have generally supported the epidemiological data and es-
tablished possible cause–effect relationships between spe-
cific environmental factors and neuronal vulnerability. For
example, folate deficiency and elevated homocysteine lev-
els can endanger neurons [20,57,58], and caloric restriction
can protect neurons [8,18,124] in models relevant to AD and
Parkinson’s disease and stroke. Thus, data suggest that the
probability of successful brain aging can be increased by
reducing environmental risk factors.
4. Successful brain aging
Promoting the maintenance of cognitive, emotive, motor
and sensory functions throughout the life-span (successful
brain aging) should be considered as the goal of scientists in
the broad field of the neurobiology of aging. This might be
accomplished by avoiding genetic and environmental fac-
tors that facilitate neuronal dysfunction and death, or by en-
hancing the ability of neurons to adapt to the aging process.
Rapid progress has been made in identifying cellular signal-
ing mechanisms that promote cell survival, neurite growth
and/or synapse formation/plasticity. A better understanding
of these signaling pathways may reveal ways of promoting
successful brain aging.
5. Neuroprotective mechanisms
Discovery of the cellular and molecular mechanisms that
promoteneuronalsurvivalandplasticityhasbeenamajorfo-
cus of research in many laboratories during the past decade.
Two major classes of intercellular signaling proteins that
are firmly established as regulators of neuronal survival and
synaptic plasticity are neurotrophic factors and cytokines.
Cell culture and in vivo models relevant to the pathogen-
esis of age-related neurodegenerative disorders have iden-
tified many different neuroprotective factors with the fol-
lowing being prominent examples: basic fibroblast growth
factor (bFGF), NGF, BDNF, NT-4, transforming growth
factor-? (TGF-?), tumor necrosis factor (TNF) and GDNF.
One or more of these factors can protect one or more pop-
ulations of brain neurons against excitotoxic, oxidative and
metabolic insults in models of stroke, AD, Parkinson’s and
Huntington’s disease [81]. In addition, signaling via cell ad-
hesion proteins such as integrins is increasingly recognized
as playing important roles in modulating neuronal survival
[32]. In general, the mechanism whereby the growth fac-
tors, cytokines and integrin signaling promote neuronal sur-
vival is by inducing the expression of genes that encode
proteins that suppress oxidative stress, stabilize cellular cal-
cium homeostasis and block apoptotic biochemical cascades
(Fig. 2). For example, bFGF, BDNF, TNF and NGF can in-
crease the production of one or more antioxidant enzymes
(Cu/Zn-SOD, Mn-SOD, glutathione peroxidase and cata-
lase) in hippocampal neurons [78,80,82]. By activating ki-
nases such as mitogen-activated protein (MAP) kinase and
protein kinase C, and transcription factors such as NF-?B
and CREB, neurotrophic factors and cytokines can mod-
ulate the expression and/or activity of subunits of gluta-
mate receptors and voltage-dependent calcium channels in
ways that promote neuronal survival and synaptic plasticity
[80,87,120]. Two other classes of neuroprotective proteins
that are upregulated by growth factors, cytokines and cell
adhesion molecules are antiapoptotic Bcl-2 family members
[9] and inhibitor of apoptosis proteins [122].
In addition to antioxidant enzymes and antiapoptotic
proteins such as Bcl-2 and IAPs, neurons express several
so-called chaperone proteins that exert prominent neuro-
protective actions. Chaperone proteins interact with many
different proteins in cells and function to ensure their
proper folding on the one hand, and degradation of dam-
aged proteins, on the other hand [27,34]. Two chaperone
proteins that have been shown to protect neurons against
injury and death in experimental models of neurodegen-
erative disorders are heat-shock protein-70 (HSP-70) and
glucose-regulated protein-78 (GRP-78) [68,125]. Expres-
sion of such chaperone proteins may be increased during

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699
Fig. 2. Examples of cellular signaling pathways that modulate neuronal
plasticity and survival during aging. BDNF: brain-derived neurotrophic
factor; trkB: high affinity BDNF receptor; PI3K: phosphatidylinosi-
tol-3-kinase; Akt: Akt kinase; TF: transcription factor; sAPP: secreted
form of amyloid precursor protein; APPR: amyloid precursor protein re-
ceptor; cGMP: cyclic guanosine monophosphate; PKG: protein lunase G;
IAP: inhibitor of apoptosis protein; TNF: tumor necrosis factor; IKK:
I kappa B lunase; Mn-SOD: manganese superoxide dismutase; NM-
DAR: N-methyl-d-aspartate receptor; Par-4: prostate apoptosis response-4;
R: receptor; PK: protein kinase; MPTP: 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine; MPP+: reactive form of MPTP.
aging as protective response [37,64,124]. It is particularly
interesting that caloric restriction, a dietary manipulation
that increases life-span and brain health-span [26,121], also
increases expression of chaperone proteins in neurons of
rats and mice [18,124].
Thefunctionofneuroprotectivesignalingpathways,chap-
erone proteins and antiapoptotic proteins in synaptic termi-
nals may be particularly important for promoting synaptic
plasticity and preventing synapse loss and neuronal death
Table 1
Examples of aging-relevant genes and environmental factors that affect synaptic homeostasis in positive or negative ways
Effect on synapsesReferences
Genes
APP (sAPP?) Enhanced plasticity, glucose transport, glutamate transport
Reduced oxidative stress, improved mitochondrial function
Impaired plasticity, disturbed calcium and oxyradical metabolism
Impaired plasticity, disturbed calcium and oxyradical metabolism
Regulate dopamine release
Perturbed dopamine release
[29,84]
APP mutations
Presenilin-1 mutations
?-Synuclein
?-Synuclein mutations
[79]
[36]
[1]
[106]
Environment
Dietary restrictionEnhanced plasticity, glucose transport, glutamate transport
Reduced oxidative stress, improved mitochondrial function
Enhanced plasticity
Enhanced plasticity
Impaired plasticity and mitochondrial function
Impaired plasticity
[19,37]
Cognitive activity
Physical activity
Trauma
Chronic stress
[43,54,105]
[17]
[2]
[112]
during aging [35,84]. Synapses are very likely to be the sites
where the impact of aging is first exerted upon the neuron
and it is therefore of great importance to understand how
genes and environment affect synaptic homeostasis. Table 1
provides some examples of studies documenting both ben-
eficial and detrimental effects of specific genetic and envi-
ronmental factors on synapses.
6. Neurorestorative mechanisms
Two conclusions that have arisen from work done in many
different laboratories during the past 10 years are that re-
generation/compensation can occur in the adult brain, and
that the brain contains populations of stem cells or neu-
ral progenitor cells (NPC) that are capable of dividing and
then differentiating into neurons or glia [101]. When axons
of neurons in the brain are damaged, sprouting of new ax-
onal processes occurs. However, in contrast to the peripheral
nervous system the brain contains a number of inhibitory
signals that often prevent successful reinnervation of target
cells [107]. In addition, when synaptogenesis does occur it
may not replace lost function because of the high degree of
specificity of neuronal connections in the brain and the fact
that many brain functions rely on “memories” based on the
past history of synaptic activity. Various neurotrophic fac-
tors and cytokines are involved in the modulation of neurite
outgrowth and synaptic recovery after brain injury [47,81].
One of the most exciting and rapidly growing areas in the
field of neuroscience is stem cell biology. The adult brain
contains two major populations of pluripotent progenitor
cells, one in the subventricular zone and the other in the
subgranular layer of the dentate gyrus of the hippocampus
[30]. These NPC cells can give rise to either neurons or
astrocytes, and there is increasing evidence that many of
the newly-generated cells survive and become functional,
although some may undergo programmed cell death. NPC
can be labeled by giving animals the thymidine analog