hanipsych, bdnf in alzh
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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
Agenda
Introduction
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)
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.
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.
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
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
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
Microscopy image of a neurofibrillary tangle, conformed by hyperphosphorylated tau protein.
Dementia
Alzheimer’s disease Neocortical Changes
Shrinkage of the cortex; not uniform
Dementia
Alzheimer’s Disease Neurotransmitter changes
Reduction in two or more transmitter systems ACh, Noradrenaline, DA, 5-HT, and glutamate receptors
Putative Causes of Alzheimer’s Disease
GeneticsTrace Metals
Increased concentration of aluminum
Immune Reactions Antibrain antibodies that cause neuronal degeneration
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
Brain Derived Neurotrophic Factor
and neuronal plasticity
increases cortical neuron survival increases cortical neuron survival sculpts glutamate innervation patternssculpts glutamate innervation patternsincreases synaptic efficacy of glutamate increases synaptic efficacy of glutamate modulates LTP in hippocampusmodulates LTP in hippocampusexpression increased during spatial memoryexpression increased during spatial memoryexpression increased by antidepressant treatmentsexpression increased by antidepressant treatmentsgenetic associationsgenetic associations: Alzheimers Disease, : Alzheimers Disease,
Parkinson’s Disease, bipolar disorder, Parkinson’s Disease, bipolar disorder, schizophreniaschizophrenia
The BDNF Gene11p1411p13CHROMOSOME 11
PROMOTER
5´
1 297 1040 1353 BP
START CODON STOP CODON
681468492
G492 A492
Val66 Met66
MAY BE EXTRACELLULARLYACTIVE AT TrkB RECEPTORS
proBDNF (32 kDa)
TRUNCATED proBDNF (28 kDa)SIGNALPEPTIDE
ACTIVITY UNKNOWN
Val66 Met66
MATURE BDNF (14 kDa)SIGNALPEPTIDE
ESSENTIAL ROLE INDEVELOPMENT, SURVIVAL
AND FUNCTION OF NEURONS
Val66 Met66
CLEAVED IN ENDOPLASMIC RETICULUM
CLEAVED IN TRANS-GOLGI NETWORK
AND/OR IMMATURE VESICLESOR
BDNF:val66metpolymor-
phism
Cells:Intracellular trafficking
and regulated secretion
Systemshippocampal processing of
memory
bipolar disorder,schizophreniaAlzheimer’s
Disease, antidepressant
effects
Behavior:complex functional
interactions and emergent
phenomena
BDNFBDNF: How do we get there from here ?: How do we get there from here ?
25%25%5%5%hippocampal
activationduring retrieval interaction of BDNF genotype
and hippocampal activation during encoding
BDNF val/met genotype, hippocampal activation and prediction of recognition accuracy
variability of recall
5%5%25%25%
Variance in memory performanceVariance in memory performance
Hariri et al J Neurosci 2003
Dietary Restriction
Cellular Stress Response
BDNFNeuroprotectionNeurogenesisSynaptic plasticity
Improved Glucose Metabolism
Resistance to Neurodegenerative Disorders
Resistance to Diabetes and Cardiovascular Disease
SSRIserotonin
Physical ExerciseCognitive Enrichment
Dietary and Behavioral Neurohormesis
Average Lifespan
Maximum Lifespan
Disease
Exercise
DietAGING
GenesMental Health
Overeating: Our Nation’s Biggest Health ProblemCardiovascular diseaseDiabetesCancersStroke
Neurodegenerative disorders?Reduced lifespan
Dietary RestrictionIncreased insulin sensitivityImproved cardiovascular risk factorsDecreased tumor incidenceIncreased cellular stress resistanceEnhanced neuronal plasticityDisease resistanceIncreased lifespan
Reduced Lifespan
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)
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.
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..
BDNF
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 arteriesThe cerebral area controls consciousness, memory, initiation of activity,
emotional response, language and word associationsNarrowing 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.
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
Effects of Aerobic Exercise on Brain
Protects against hyperinsulinemia and insulin resistanceIncreased dopamine levels in the brainIncreases cerebral vasculature and blood flow
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
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.
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