1. Adult Neurogenesis and Brain Dysfunctions
Abhishek Das1∗
1
BS-MS 20131056, IISER Pune
∗
To whom correspondence should be addressed; E-mail: abhishek.das@students.iiserpune.ac.in
This document briefly describes the process of adult neurogenesis and how
altered neurogenesis gives rise to Alzheimers Disease(AD) and other neuro-
logical disorders.Human studies often does not directly measure adult neuro-
genesis but instead it measures 1) cell proliferation (which usually correlates
with neurogenesis in rodents, but assumes that proliferation results in surviv-
ing neurons in humans), 2) stem cell markers (such as nestin, which correlates
with neurogenesis only if they indeed divide and produce new neurons), 3)
immature neurons, 4) other factors that correlate with neurogenesis, such as
blood flow or stem cell biomarkers. With the help of these techniques the essay
describes adult neurogenesis and it’s role in certain brain disorders.
Introduction
”In adult centers the nerve paths are something fixed, ended, immutable. Everything may die,
nothing may be regenerated.”- Santiago Ramon Y Cajal, ”Degeneration and Regeneration in
the Nervous System,” 1928.
1
2. This long-held belief, first proposed by Cajal, held that human brain neurons were unique
because they lacked the ability to regenerate. But through years of research by eminent scientists
like Altman, Kaplan and Nottebohm in 1998, the journal Nature Medicine finally published a
report indicating that neurogenesis, the growth of new brain cells, does indeed occur in humans.
Adult neurogenesis is a dramatic form of brain circuit plasticity associated with the forma-
tion of functional, mature neurons from neural stem cells in specific brain regions in adults. In
these regions, new neurons are generated throughout life and integrated into established neu-
ronal circuits. In fact many brain diseases such as Alzheimers disease (AD), epilepsy and other
neurological and neuropsychiatric diseases have been seen to be caused by dysfunctional neu-
rogenesis. .
Adult Neurogenesis in SVZFig.1
Stem cells1
are found in distinct environment-maintained by secreted molecules and their bind-
ing on cell-surface receptors. In mammalian brains, new neurons are generated in sub-ventricular
zone (SVZ)-cell dense region adjacent to ventricular spaces in cortical hemisphere along with
sub-ventricular regions of mid-brain and spinal cord. 3 classes of cells are found in mammalian
SVZ- Neural stem/progenitor cells (NSPCs), transit-amplifying (TA) cells and neuroblasts.
NSPCs are found closely to blood vessels indicating they are also controlled via circulation
alongside cellular crosstalk. These stem cells divide slowly and symmetrically giving rise to
astrocytes, neurons, glial cells, etc. In order to do this, stem cells must give rise to intermediate
precursor cells (TA cells).
Neuroblasts are no longer competent to divide and move away from SVZ to regions of
mature neuron/glia.
This migration from anterior SVZ to maturation region like olfactory bulb (OB) or hip-
pocampal dentate gyrus7
(DG) is considerable and a special migratory route, defined by distinct
2
3. subset of glial cells is present and called Rostral Migratory Stream (RMS).Once at OB, neu-
roblasts differentiate into distinct types of olfactory neurons; and into newborn granule cells in
DG.
Adult Neurogenesis in HippocampusFig.2
In the adult hippocampus2
, neuroblasts reside in the sub-granular zone (SGZ) of the DG and
give rise to granule cell neurons in a multistep process.
Quiescent NSPCs, i.e. Type 1 cells, extend a radial process through the granule cell layer
(GCL) into the molecular layer (ML). These NSPCs can be activated to generate non-radial
NSPCs. Immature neurons migrate up into the GCL and over a period of 3 weeks newborn
granule cell neurons project out a large dendritic arbor into the ML and an axon into the hilus
that terminates on target cells in the hilus and area CA38
.
During maturation, newly formed DG cells differ substantially from their older counterparts
in terms of electrophysiological properties.
Alzheimers disease and NeurogenesisFig.3
Alzheimers disease (AD) is an age-related neurodegenerative disease characterized by progres-
sive loss of memory and deterioration of cognitive functions. This kind of disorder is usually
associated with difficulties in learning, performance speed, recall accuracy and/or problem solv-
ing.
Of the neurogenic zones in the adult brain, adult hippocampal neurogenesis attracts the most
attention, because it is involved in higher cognitive function, most notably memory processes,
and certain affective behaviours.
Some important neuropathological features of AD are interneuronal accumulation of neu-
rofibrillary tangles (NFT), senile plaques (SP) and massive neuronal death. These pathologies
3
4. are evident in specific, vulnerable brain areas and the hippocampus is one of the earliest to be
affected.
NFTs are aggregates of hyperphosphorylated tau protein that are most commonly known as
a primary marker of AD while SPs are extracellular deposition of amyloid-β(Aβ)proteins in
the grey matter of the brain(which is believed to be an important trigger for AD pathogenesis).
These senile plaques are made up largely of 38-43 amino acid Aβ peptides, which are liber-
ated from a larger integral membrane protein, amyloid precursor protein (APP), by sequential
β−andγ− secretase cleavage. These polypeptides tend to aggregate and are believed to be neu-
rotoxic. The vast majority of AD cases appear in late onset sporadic form. Aging is the greatest
environmental risk factor of the sporadic form and the most important genetic risk factor is the
presence of the 4 allele in apolipoprotein E (ApoE4).
Rare, familial, early-onset autosomal dominant forms of AD (FAD) are found to involve
mutations in the genes encoding APP and presenilins (PS1 and PS2). Cleavage of APP at
the N-terminus by β -secretase and at the C-terminus by the γ-secretase complex constitutes
the amyloidogenic pathway, which yields the APP intracellular domain (AICD) fragment in
addition to Aβ. In the non-amyloidogenic pathway, α-secretase cleaves APP within the Aβ
domain, which results in generation of a soluble fragment of APP (sAPPa) and a membrane
bound carboxyl-terminal fragment, thereby precluding the formation of Aβ which causes AD.
Conclusion
The process of neurogenesis is controlled by our DNA. A specific gene codes for the production
of a protein, brain-derived neurotrophic factor (BDNF) which plays a key role in creating new
neurons. As is explained above, studies reveal decreased BDNF in a variety of neurological
conditions. Efforts are currently made to understand the disease-associated role of neurogenesis
and to use this knowledge to develop novel strategies to harness NSPCs for endogenous repair
4
5. to disease symptoms. The development of non-invasive detection of adult neurogenesis and
specific biomarkers might provide new means of early diagnosis of AD.
References and Notes
1) Stem cells are undifferentiated biological cells that can differentiate into specialized cells
and can divide (through mitosis) to produce more stem cells. They are found in multicellular
organisms.
2) The hippocampus is a major component of the brains of humans and other vertebrates.
Humans and other mammals have two hippocampi, one in each side of the brain. It belongs to
the limbic system and plays important roles in the consolidation of information from short-term
memory to long-term memory and spatial navigation. The hippocampus is located under the
cerebral cortex in primates it is located in the medial temporal lobe, underneath the cortical
surface.
3) http://www.nature.com/subjects/adult-neurogenesis
4) Braun, S. M. G., Jessberger, S. (2014). Adult neurogenesis and its role in neuropsychi-
atric disease, brain repair and normal brain function. Neuropathology and Applied Neurobiol-
ogy, 40(1), 312. doi:10.1111/nan.12107
5) Mu, Y., Gage, F. H. (2011). Adult hippocampal neurogenesis and its role in Alzheimers
disease. Mol Neurodegener, 6(1), 85. doi:10.1186/1750-1326-6-85
6) Adult Neurogenesis and Neuropathology Lecture by Nixon M. Abraham, IISER Pune
5
6. 7) The dentate gyrus is part of the hippocampus and/or hippocampal formation. The dentate
gyrus is thought to contribute to the formation of new episodic memories. It is notable as being
one of a select few brain structures currently known to have high rates of neurogenesis in adult
rats.
8) The hippocampus is composed of multiple subfields. The terms most frequently used are
dentate gyrus and the cornu ammonis(CA). The dentate gyrus contains the fascia dentata and
the hilus, while CA is differentiated into fields CA1, CA2, CA3, and CA4.
9) Wikipedia Information(Verified)
10) Studies of Adult Hippocampal Neurogenesis in Humans by Jason Snyder
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