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.