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The authors thank members of the McAllister laboratory for ongoing
discussions about the topics covered in this Review. Due to journal
guidelines, we were not permitted to cite many of the original reports,
and we apologize to those whose articles are not referenced. Please
see referenced reviews for primary source articles. A.K.M. and
M.L.E. are listed as inventors on a patent application (U.S. Patent
Application 61/989, 791) entitled “Methods for Diagnosing and
Treating Neuroimmune-Based Psychiatric Disorders.” M.L.E. has been
supported by a Stanley and Jacqueline Schilling Neuroscience
Postdoctoral Research Fellowship, a Dennis Weatherstone Predoctoral
Fellowship from Autism Speaks (no. 7825), the Letty and James
Callinan and Cathy and Andrew Moley Fellowship from the ARCS
(Achievement Rewards for College Scientists) Foundation, and a
Dissertation Year Fellowship from the University of California Office of
the President. A.K.M. is supported by grants from the National
Institute of Neurological Disorders and Stroke (R01-NS060125-05),
the National Institute of Mental Health (P50-MH106438-01),
the Simons Foundation (SFARI no. 321998), and the University
of California Davis Research Investments in Science and
How neuroinflammation contributes
Richard M. Ransohoff
Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic
lateral sclerosis, and frontotemporal lobar dementia are among the most pressing problems of
developed societies with aging populations. Neurons carry out essential functions such as
signal transmission and network integration in the central nervous system and are the main
targets of neurodegenerative disease. In this Review, I address how the neuron’s environment
also contributes to neurodegeneration. Maintaining an optimal milieu for neuronal function
rests with supportive cells termed glia and the blood-brain barrier. Accumulating evidence
suggests that neurodegeneration occurs in part because the environment is affected during
disease in a cascade of processes collectively termed neuroinflammation. These observations
indicate that therapies targeting glial cells might provide benefit for those afflicted by
The human central nervous system (CNS) might represent the most complex entity in existence, although conclusive evidence to support or falsify that hypothesis will probably forever be elusive. Nonetheless,
the CNS is beyond question the most elaborate
system of which we have daily experience. CNS
disorders alter and often degrade the structure
and function of this intricate organ. Neurodegeneration is a common (but not invariable)
component of CNS disorders and includes processes by which previously established CNS functions such as mobility, memory and learning,
judgment, and coordination are progressively
lost. Neurodegenerative diseases primarily occur
in the later stages of life, positioning time as an
essential cofactor in pathogenesis of the major
neurodegenerative disorders in a mechanism-driven fashion (1–3). The achievements of medicine
and public health efforts in reducing early- and
midlife mortality from certain cancers, infectious
diseases, and cardiovascular disorders mean that
a larger number of individuals are aging and
therefore susceptible to neurodegenerative disease by virtue of their survival. The large cohort
of aging people in the developed world threatens
society with a substantial burden of care for those
afflicted with neurodegeneration (4). Moreover
and most poignantly, these diseases rob affected
persons of those attributes that make long lives
worth living: thinking, feeling, remembering,
deciding, and moving. Here I consider neuroinflammation in neurodegeneration, a topic that
comprises most of the nonneuronal contributors
to the cause and progression of neurodegenerative
disease. The study of this topic is animated by our
hope that meaningful action, in the form of novel
treatments, will follow understanding.
What is neurodegeneration?
Neurons are the primary cells of the CNS and
endow it with its distinctive functions. Connec-
tions between neurons are enacted at synapses,
where neurotransmitters are released in quanta
to deliver an excitatory or inhibitory signal to
the synaptic-target neuron. Cell processes that
deliver these signals are termed axons, whereas
dendrites receive synaptic inputs. Each of the
~1011 neurons in the human brain integrates
many synaptic inputs from other neurons and,
for each input received, may or may not initiate
an axonal action potential and thereby provide
synaptic input to its target neuron—a system
comprising 1015 connections in all.
Neurodegeneration by definition disturbs the
properties of the CNS and therefore affects neuronal function, as well as the structure or survival of neurons. Unlike primary cells from skin,
the liver, or muscle, neuronal cells of the CNS
do not regenerate after damage by disease, ischemia (deprivation of oxygen, glucose, or blood
flow), or physical trauma. Because the complexity
of the human CNS is so great, neurodegenerative
disorders that derange its function have been
challenging to understand and treat: No therapeutics ameliorate the natural course of neurodegenerative disease.
Major neurodegenerative diseases include
Alzheimer’s disease ( AD), frontotemporal lobar
dementia (FTLD), Parkinson’s disease (PD), and
amyotrophic lateral sclerosis (ALS). Individuals
diagnosed with multiple sclerosis (MS) are also
at risk of developing a neurodegenerative course,
typically at later stages of the disease; such cases
are termed progressive MS (P-MS). One might
consider that AD, PD, and ALS are primary
neurodegenerative diseases, in which the initial
Biogen, 225 Binney Street, Cambridge, MA 02142, USA.
been famously difficult to
define in relation to