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December 2011.

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The brain on steroids: Sonic Hedgehog to the rescue
Preterm newborns often develop systemic illness and lung disease
requiring treatment with glucocorticoids (GC). Recent data in
humans suggest that while prenatal treatment with steroids may
not be harmful, postnatal treatment may affect development of
the cortex and cerebellum. In this study, the investigators propose
a possible mechanism, and treatment, for the deleterious effects
of postnatal steroids. Smoothened–Sonic hedgehog signaling
pathway drives cerebellar granule cell proliferation during
development and this pathway is disrupted by glucocorticoid
administration. The investigators previously showed that glucocorticoids inhibit Sonic hedgehog–Smoothened (Shh-Smo)
signaling through induction of the 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2) pathway. Using a novel compound,
SAG, an agonist of Smoothened, Heine and colleagues were able
to show that SAG antagonized GC anti-proliferative effects in
primary cerebellar granule neuronal precursor cultures, crossed
the blood-brain barrier to activate Sonic hedgehog targets in the
mouse cerebellum, and prevented the growth-inhibitory effects of
GCs. In addition, they found that the transient (1-week-long)
SAG treatment of neonatal animals was well tolerated, did not
prevent the beneficial effects of glucocorticoids on lung development, and did not promote tumor formation in the animals. In
another study in human preterm babies cited in the same issue,
Tam and colleagues, using serial magnetic resonance imaging
examinations near birth and again near term-equivalent age in
172 preterm neonatal infants, showed a significant effect of
postnatal GCs on cerebellar, but not cerebral, brain growth. After
adjusting for associated clinical factors, postnatal, but not prenatal, treatment with GCs resulted in reduction in cerebellar
volume. These companion papers demonstrate that there is a
modifiable risk factor for impaired brain development in vulnerable preterm newborns, and that a treatment may exist to modify
the adverse effects if the GC must be given to protect other organ
systems (Sci Transl Med 2011;3:105).
Genetic determinants of intellectual disability
In the largest published study of this type so far, Najmabadi
and colleagues describe a deep genomic exploration of autosomalrecessive intellectual disability (AIRD) using a combination of
homozygosity mapping, exon enrichment of candidate genes,
and next-gen sequencing. The study included 136 consanguineous families, most recruited in Iran where approximately 40%
of the families are consanguineous and about two-thirds of the
population is 30 years of age or younger. The screen revealed
mutations in 23 genes previously implicated in intellectual
disability or related neurological disorders, as well as single,
putative disease-causing variants in 50 novel candidate genes.
The results provide an updated catalog of mutations, confirming the extreme genetic heterogeneity that characterizes AIRD,
and suggest that the total number of genes affecting intellectual
disability may run into the thousands. Surprisingly, relatively
few of the identified mutations are in synapse- or neuron-
C 2011 American Neurological Association
A10 V
specific genes, and they are vastly outnumbered by ubiquitously
expressed genes with central cellular functions, such as DNA
transcription and translation, protein degradation, mRNA
splicing, energy metabolism as well as fatty-acid synthesis and
turnover, which are obviously important for normal brain
development and function (Nature 2011;478:57-63).
Getting rid of old cells is good for you
Recent evidence suggests that senescent cells secrete factors that
promote age-related tissue dysfunction. In this paper the
authors used a ‘‘Trojan horse’’ transgenic strategy to eliminate
senescing cells in a progeroid mouse model and delayed agerelated pathology. The strategy involved design of an FK506Caspase 6 fusion protein driven by a minimal promoter for the
gene p16Ink-4a, which encodes a cyclin-dependent kinase inhibitor that causes growth arrest and increases in expression during
aging. ‘‘INK-ATTAC’’ ( INK apotosis through targeted activation
of caspase) mice expressing this transgene were crossed with
BubR1H/H hypomorphic mice; BubR1 encodes a member of
the mitotic checkpoint and ensures accurate chromosome segregation. These mice have a shortened lifespan and premature
senescence of several tissues with loss of muscle mass, cataracts,
fat loss, and impaired wound healing. These mice also accumulate p16Ink-4a in tissues that age prematurely. Treating BubR1H/H
mice that express INK-ATTAC with the drug AP20187, a
synthetic drug that causes dimerization and activation of the
FK506-Caspase 6 fusion protein, eliminated p16Ink-4a- expressing
cells and delayed onset of sarcopenia, cataracts, and loss of
adipose tissue. Initiation of treatment later in life showed that the
effect of AP20187 was to delay progression of senescence rather
than reverse ageing. The beneficial effects of eliminating senescent cells only occurred in tissues that normally express p16Ink-4a
as they age; cardiac arrhythmias and arterial wall stiffening, which
are p16Ink-4a-independent, were not altered. These findings
strongly support the hypothesis that senescing cells produce factors that contribute to age-related dysfunction and feed forward
to promote the aging process. Elimination of senescing cells may
be a useful approach for treating or delaying age-related disease
(Nature 2011;479:232-6).
More merging of man and machine: offloading
memories to the Internet
The near ubiquitous access to the Internet by clinicians and
scientists, let alone the majority of members of our society, has
clearly influenced the approach that people are using to remember things. Sparrow and colleagues hypothesized that having
access to computers (or similar data storage devices) is associated with less of a need to commit to memory formation internally (i.e. using one’s own hippocampal/cortical long-term
memory systems). To address this, they carried out four fascinating experiments that showed that, when faced with difficult
questions, people are primed to think about computers and
that when people expect to have future access to information,
they have lower rates of recall of the information itself and
enhanced recall instead for where to access it. For example, in
one of the experiments participants were asked to read 40 memorable trivia statements of the type that one would look up online,
and they then typed the statements into a computer. However,
half the participants believed the computer would save what was
typed and half believed the information would be erased.
Furthermore, half of the participants in each of the saved and
erased conditions were asked explicitly to try to remember the information. After the reading and typing task, participants wrote
down as many of the statements as they could remember. The
results showed that those who believed the computer erased what
they typed had the best recall compared with those who believed
the computer would be their memory source. Of note, the main
effect of the instruction to explicitly remember or not was not
significant, (similar to previous findings in the learning). Thus,
participants were more affected by the cue that information
would or would not be available to them later, regardless of
whether they thought they would be tested on it. These and the
other study results verify that the availability of the Internet and
external memory storage devices are, indeed, modifying the strategies we are using to manage the information we deem relevant
to our lives. This phenomenon is undoubtedly relevant to the
approaches we should take in educating the newest generation of
learners who have been connected to the Internet from the time
of their earliest memories (Science 2011;333:776-778).
in the Annals...
Mice inoculated intracerebrally with mouse brain homogenate infected with a particular strain of scrapie agent
developed amyloid and neuritic plaques and amyloid tubercles along the injection track, solid wall-like infiltrations at
the injection site, or both, Our observations implicate an infectious agent in the localized formation of the amyloid and
the neuritic plaque—the leading pathological change found in normal elderly people and animals and in patients with
senile dementia of the Alzheimer type. Further, these studies indicate that microglia appear to play a central role in the
pathogenesis of amyloid formation and could be involved in the processing, production, and assembly of the fibers.
December 2011
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