ANALISIS

Modulation of Brain-Derived Neurotrophic Factor

(BDNF)-Induced Trophic Signalling
as an Alternative Treatment
for Alzheimer’s Disease
Muthmainah
Department of Anatomy and Embryology,
Faculty of Medicine, Sebelas Maret University, Surakarta

ABSTRACT
Alzheimer’s disease (AD) is a disorder of synaptic function and neuronal degeneration characterized by decline in memory and cognition
as well as changes of personality. Brain-Derived Neurotrophic Factor (BDNF) is a major modulator of synaptic plasticity and is an
acknowledged pharmacological target for the treatment of a range of neurological disorders including AD. Attempts to supply BDNF
exogenously are limited by side effects. An alternative strategy to enhance BDNF-induced trophic signalling is through amplification of neural
response to the reduced supply of endogenous BDNF found in AD.

Keywords: Alzheimer’s disease, alternative treatment, BDNF, trophic signalling

ABSTRAK
Penyakit Alzheimer adalah kelainan fungsi sinaptik dan degenerasi neuron yang ditandai oleh penurunan fungsi kognitif dan memori serta
perubahan kepribadian. Brain-Derived Neurotrophic Factor (BDNF) adalah modulator plastisitas sinaptik utama dan telah diakui merupakan sasaran
pengobatan berbagai kelainan neurologis termasuk penyakit Alzheimer. Usaha memberikan BDNF eksogen terkendala oleh berbagai efek
samping. Alternatif lain meningkatkan sinyal trofik BDNF adalah dengan amplifikasi respons saraf terhadap terbatasnya kadar BDNF yang
sering dijumpai pada penyakit Alzheimer. Muthmainah. Modulasi Sinyal Trofik Brain-Derived Neurotrophic Factor (BDNF) sebagai
Terapi Alternatif Penyakit Alzheimer.

Kata kunci: Penyakit Alzheimer, pengobatan alternatif, BDNF, sinyal trofik

INTRODUCTION
Alzheimer’s disease (AD) is the most common
form of dementia characterized by synaptic
function disorder and neuronal degeneration.
The symptoms include a decline in memory
and cognitive performance as well as
personality changes. However, the etiology
of the disease is not well understood and
definitive diagnosis can only be made after
autopsy. The key pathological hallmark of
AD is the accumulation of amyloid-beta
(Aß) plaques and neurofibrillary tangles
composed of hyperphosphorylated tau
throughout the brain.
The prevailing theory of AD states that Aß
accumulation is central to disease etiology;
the brain overproduces or fails to degrade level of neurotrophin that are crucial for
the Aß peptide. In about 5% cases, genetic neuronal activity and survival.3 Therefore,
cause underlies this overproduction.
However, there has been no clear answer for
the remaining 95% patients. Recent finding
shows that Aß oligomeric aggregates are
toxic and can inhibit synaptic activity and
promote neuronal degeneration.2 There
have been attempts to treat AD by removing
Aß plaques but failed in clinical trial. Another
proposed mechanism to abolish the cognitive
decline is to enable circuit rerouting by
facilitating long-term potentiation (LTP) as such
to enhance synaptic plasticity.
Figure 1. Pathological hallmark of Alzheimer’s disease.
One current major hypothesis underlying Aggregation of Aß in the extracellular compartment and
cognitive impairment in AD is the reduced neurofibrillary tangles is a common feature in AD.1

Alamat korespondensi email: mutmainah.fkuns@gmail.com

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neurotrophins such as brain-derived
neurotrophic factor (BDNF) have been a
pharmacological target for treating AD.
Furthermore, BDNF is also a major mediator
of synaptic and circuit plasticity.4,5 However,
providing in vivo BDNF to treat impaired
brain function is quite challenging because
supplying exogenous BDNF has been shown
to be ineffective.6 Thus, an alternative strategy
must be developed to correct the reduced
neurotrophin signalling in AD.
The Neurotrophin Family and Their
Associated Receptors
Neurotrophins including BDNF, nerve
growth factor (NGF), neurotrophin-3 (NT-3)
and neurotrophin-4 (NT-4) are subfamily of
neurotrophic factors (NTFs) that regulate
many aspects of neuronal development
and function. This includes neurogenesis
and differentiation, neurite outgrowth,
synaptogenesis and synaptic plasticity, and
circuit maintenance.7 In particular, BDNF is
crucial in controlling normal adult brain
function, being the major activity-dependent
modulator of neuronal and synaptic activity
in the brain.
There are three receptors that interact with
this neurotrophin family. Each of the receptor
has specificity for a particular neurotrophin
but also exhibits some overlapping
Figure 2. The neurotrophin family and their associated receptors. TrkA prefers NGF as its ligand. TrkB binds to both BDNF
and NT- 4/5, and TrkC prefers NT-3 as its binding partner. Formation of p75NTR-Trk receptor complex activates trophic signalling
(survival) whereas p75NTR activation mediates cell death.10
CDK-230/ vol. 42 no. 7, th. 2015
interaction with other neurotrophins.8
The neurotrophin-mediated signalling is
mediated by tropomyosin-related kinase (Trk)
receptors, p75neurotrophin receptors (p75NTR),
and the pro-neurotrophin receptor, sortilin.
Neurotrophins can promote cell survival by
activating Trk receptor and cause cell death
by activating p75NTR. The Trk receptor family
is comprised of (i) TrkA which prefers NGF as
its ligand (ii) TrkB which binds to both BDNF
and NT- 4/5, and (iii) TrkC which prefer NT-3 as
its binding partner. Recent studies showed that
cholinergic basal forebrain neurons expressing
TrkA receptors respond to NGF and thus
promote and maintain synaptic transmission.
In hippocampus, binding of BDNF via TrkB
receptors at postsynaptic dendrite maintains
long-term potentiation, a mechanism that
underlies learning and memory formation.
Thus, a reduction of either NGF or BDNF, or a
change in the levels of TrkA or TrkB receptors,
might lead to the impairment of memory
formation and neuronal degeneration. As a
result, cognitive decline which is a common
symptom in AD will occur.9
Reduced Levels of Neurotrophins are
Associated with AD
Reduced level of both NGF and BDNF are
common features in AD. It is reported that
the amount of NGF in serum is significantly
reduced in AD patients compared to elderly
ANALISIS
controls.11 In addition, BDNF levels both in
plasma and serum are also reduced in AD
patients as well as subjects with mild cognitive
impairments compared with controls.3 It is
suggested that early memory dysfunction
seen in AD is caused by decreased level of
BDNF hippocampus. Evidence to support this
includes substantially reduced BDNF mRNA
levels in the hippocampus and parietal
cortex of AD patients as well as decreased
BDNF protein levels in hippocampus,
temporal, frontal, and parietal cortex.12-14 In
animals, loss of either BDNF or TrkB receptors
impairs synaptic plasticity and gives rise to
behavioural changes including cognitive
deficits.15 In humans, reduced BDNF
expression is also associated with cognitive
impairment and neurological disorder ranging
from AD to mood disorder such as depression
and anxiety.6
BDNF as a Pharmacological Target for
Treating AD
Disease severity in AD correlates well with
the degree of synaptic loss in the brain.
Enhancing synaptic plasticity by facilitating
LTP is one of the strategies to combat the
cognitive decline. As a major mediator
of synaptic and circuit plasticity, BDNF is
acknowledged as a pharmacological target
for the treatment of a range of neurological
disorders including AD (for comprehensive
review see 6, 16). In animal, treatments with
BDNF or its analogues can reawaken critical
periods of brain organisation as well as
promote cognitive function.4,6,17 Furthermore,
in vivo and in vitro experiments show that
BNDF can overcome cellular and neuritic
degeneration triggered by Aß.16,18 Thus,
maintaining the level of circulating BDNF
is considered a biomarker for resistance to
cognitive decline.19-21
Higher serum BDNF levels may give
protection against dementia and AD.
Considering the fact that exercise and
caloric restriction elevated BDNF level both
in the brain and blood, raised BDNF level
may be responsible for the positive effects
of this lifestyle on the occurrence and the
progression of AD.21 Thus, it is not surprising
that BDNF is a potential target for the
treatment of various neurological disorders
including AD.6,16 The ability to provide
effective concentrations of BDNF in vivo is
crucial for treating impaired brain function.
535
 ANALISIS

However, this is quite challenging due to the
fact that the permeability of neurotrophins
across the blood brain barrier is minimal.
Direct injection of BDNF results in poor tissue
permeability while intratechal administration
induces deleterious side effects including
weight loss. Another approach is through
gene delivery that has been successfully
performed in clinical trials. However, control
of the introduced gene is a major constraint
in the application of this method.6 Thus,
further investigation should be done to find
the best method to deliver exogenous BDNF
effectively. Alternatively, rather than supplying
exogenous BDNF, amplifying the neuronal
response to limited amount of endogenous
BDNF might be one of the solution.
Conclusion
Alzheimer’s disease (AD) is a disorder
of synaptic function and neuronal
degeneration that can increase the burden
of our health care system. The disease is
characterized by a decline in memory and
cognitive performance as well as changes
to personality. BDNF is an acknowledged
pharmacological target for the treatment of a
range of neurological disorders including AD.
Attempts to supply BDNF exogenously are
limited by the side effects. As an alternative,
amplification of the neural response to limited
amount of endogenous BDNF can be a focus
for research.

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