2. BDNF May Protect Against Alzheimer's
Prof. Hani Hamed Dessoki, M.D.Psychiatry
Prof. Psychiatry
Chairman of Psychiatry Department
Beni Suef University
Supervisor of Psychiatry Department
El-Fayoum University
APA member

5. Agenda
Introduction

6. Brain-Derived Neurotrophic Factor (BDNF)
BDNF Important for neurons to grow and connect to each other,
and contributes to long-term potentiation
Both are part of "neural plasticity" = the ability of the brain to
change as a result of experience
Shown in aplysia that long term memories cannot be formed
when BDNF is blocked
(University of California - Irvine (2006, September 6). Proteins Necessary For Brain Development Found To Be Critical For
Long-term Memory. ScienceDaily. Retrieved May 5, 2011, from
http://www.sciencedaily.com/releases/2006/09/060905225522.htm)

7. Introduction
 Higher blood levels of brain-derived neurotrophic factor
(BDNF) appear to protect against Alzheimer's disease
(AD) and other types of dementia.
 Blood levels of BDNF might be used to help predict risk
for AD in older adults. Or giving BDNF to older people
might prevent or counter AD symptoms.
 BDNF targets the cortical cells themselves, preventing
their death, stimulating their function and improving
learning and memory.

8. Introduction
 Higher serum BDNF levels may protect against future
occurrence of dementia and AD.
 BDNF has a role in the biology and possibly in the
prevention of dementia and AD, especially in select
subgroups of women and older and more highly educated
persons.

9. Dementia
DSM-IV-R
 Memory and other cognitive deficits
 Impairment in social and occupational functioning
Degenerative dementias
 Intrinsic to the nervous system
 Affects the CNS selectively
Nondegenerative dementias
 Diverse etiologies

11. Dementia
Alzheimer’s disease
 Most prevalent form of dementia
 Neuritic Plaques
 Found in the cortex
 Positively correlated with cognitive decline
 Amyloid surrounded by degenerative cellular fragments
 Paired Helical Filaments
 Found in the cortex and hippocampus

12. Alzheimer's disease is characterized by a build-up of proteins in the brain.
Though this cannot be measured in a living person, extensive autopsy
studies have revealed this phenomenon. The build-up manifests in two
ways:
Plaques– deposits of the protein beta-amyloid that
accumulate in the spaces between nerve cells
Tangles – deposits of the protein tau that accumulate
inside of nerve cells

13. Microscopy image of a neurofibrillary tangle, conformed by
hyperphosphorylated tau protein.

14. Dementia
Alzheimer’s disease
 Neocortical Changes
 Shrinkage of the cortex; not uniform

16. Dementia
Alzheimer’s Disease
 Neurotransmitter changes
 Reduction in two or more transmitter systems
 ACh, Noradrenaline, DA, 5-HT, and glutamate receptors

17. Putative Causes of
Alzheimer’s Disease
Genetics
Trace Metals
 Increased concentration of aluminum
Immune Reactions
 Antibrain antibodies that cause neuronal degeneration

18. Putative Causes of
Alzheimer’s Disease
Blood Flow
 Decrease in blood flow to the brain
Abnormal Proteins
 Increased production of abnormal proteins that
accumulate in the brain

19. Brain Derived Neurotrophic Factor
and neuronal plasticity
increases cortical neuron survival
sculpts glutamate innervation patterns
increases synaptic efficacy of glutamate
modulates LTP in hippocampus
expression increased during spatial memory
expression increased by antidepressant
treatments
genetic associations: Alzheimers Disease,
Parkinson’s Disease, bipolar disorder,
schizophrenia

20. The BDNF Gene
11p13
CHROMOSOME 11
PROMOTER
1
297
468
492
11p14
681
1040
1353 BP
5´
START CODON
MAY BE EXTRACELLULARLY
ACTIVE AT TrkB RECEPTORS
G492 → A492
⇓
Val66 → Met66
CLEAVED IN ENDOPLASMIC RETICULUM
Val66 → Met66
SIGNAL TRUNCATED proBDNF (28 kDa)
PEPTIDE
ACTIVITY UNKNOWN
OR
STOP CODON
proBDNF (32 kDa)
CLEAVED IN TRANS-GOLGI
NETWORK
AND/OR IMMATURE VESICLES
Val66 → Met66
SIGNAL
PEPTIDE
MATURE BDNF (14 kDa)
ESSENTIAL ROLE IN
DEVELOPMENT, SURVIVAL
AND FUNCTION OF NEURONS

21. BDNF: How do we get there from here ?
BDNF:
Cells:
val66met
polymor- Intracellular
trafficking
phism
and regulated
secretion
bipolar disorder,
schizophrenia
Alzheimer’s
Disease,
antidepressant
effects
Behavior:
Systems
hippocampal complex functional
processing of interactions and
emergent
memory
phenomena

22. BDNF val/met genotype, hippocampal
activation and prediction of recognition accuracy
Variance in memory performance
variability of recall
5%
25%
25%
5%
hippocampal
activation
during retrieval interaction of BDNF genotype
and hippocampal activation
during encoding
Hariri et al J Neurosci 2003

23. Dietary and Behavioral Neurohormesis
Dietary Restriction
Physical Exercise
Cognitive Enrichment
Cellular Stress Response
serotonin
Neuroprotection
Neurogenesis
Synaptic plasticity
BDNF
Resistance to Neurodegenerative Disorders
Resistance to Diabetes and
Cardiovascular Disease
SSRI
Improved Glucose
Metabolism

24. Overeating: Our Nation’s Biggest Health Problem
Cardiovascular disease
Diabetes
Cancers
Stroke
Neurodegenerative disorders?
Reduced lifespan
Disease
AGING
Genes
Exercise
Diet
Mental Health
Reduced Lifespan
Average Lifespan
Maximum Lifespan
Dietary Restriction
Increased insulin sensitivity
Improved cardiovascular risk factors
Decreased tumor incidence
Increased cellular stress resistance
Enhanced neuronal plasticity
Disease resistance
Increased lifespan

25. DIETARY LIPIDS AND AD
Dietary cholesterol, saturated fats and trans fats may increase the risk of
AD
(Notkola et al., Neuroepidemiology. 1998; 17:14-20.; Evans et al., Neurology. 2000; 54:240-2.; Morris et al., Arch Neurol.
2003; 60:194-200),
High cholesterol diet increases amyloidogenic processing of APP and
Abeta accumulation in brain cells
(Sparks et al., Exp Neurol. 1994; 126:88-94; Howland et al., J Biol Chem. 1998; 273:16576-82; Refolo et al., Neurobiol Dis.
2000; 7:321-31; .George et al., Neurobiol Dis. 2004; 16:124-132)
Statins may lower the risk of AD
(Wolozin et al., Arch Neurol. 2000; 57:1439-43; Jick et al., Lancet. 2000; 356:1627-31)
Statins may reduce Abeta levels in AD patients
(Simons et al., Ann Neurol. 2002; 52:346-50)
DHA (docosahexaenoic acid) levels are decreased in AD and DHA suppresses amyloid an
neuronal pathology in APP mutant mice
(Tully et al., Br J Nutr. 2003; 89:483-9; Calon et al., Neuron. 2004; 43:633-45)

26. BDNF
Cheng, A., S. Wang, M. S. Rao and M. P. Mattson (2002) Nitric oxide acts in a
positive feedback loop with BDNF to regulate neural progenitor cell proliferation
and differentiation in the mammalian brain. Dev. Biol. 258: 319-333..
Lee, J., K. Seroogy and M. P. Mattson
(2002) Dietary restriction enhances
neurotrophin expression and neurogenesis
in the hippocampus of adult mice. J.
Neurochem. 80: 539-547.

27. Exercise and brain blood vessel growth
In people ages 60-80, those who aerobically exercised 3+ hours a week
over the course of 10 years showed:
An increase in the number of large blood vessels in the cerebral
region of the brain
An increase in blood flow in the 3 major cerebral arteries
The cerebral area controls consciousness, memory, initiation of activity,
emotional response, language and word associations
Narrowing and loss of blood vessels may be associated with cognitive
decline
Rahman, Feraz, et. al (2008). Study presented at Radiological Society of North America;
UNC Chapel Hill researchers.

28. Effects of Aerobic Exercise on Brain
 Delay or reverse cerebral structural & functional
changes*
 Delay beta-amyloid accumulation*
 Improves memory*
 Increases brain-derived neurotrophic factor
(BDNF): a neurotrophin associated with
learning, cell health

29. Effects of Aerobic Exercise on Brain
Protects against hyperinsulinemia and insulin
resistance
Increased dopamine levels in the brain
Increases cerebral vasculature and blood flow

30. Future Directions
Blood levels of BDNF might be used to help
predict risk for AD in older adults.
Giving BDNF to older people might prevent or
counter AD symptoms (Lithium???).
Psychiatric News , 2013

31. Take Home Message
Higher blood levels of brain-derived neurotrophic
factor (BDNF) appear to protect against
Alzheimer's disease (AD) and other types of
dementia.