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Alzheimer's disease
Eman youssif
The content:
Structure of the brain
Important proteins in our brain
Alzheimer’s disease
Structure of the brain:
Cerebrum and cerebellum
Cerebrum:
Frontal lobe
Parietal lobe
Temporal lobe
Occipital lobe
>>>>>>>>>>
Brain stem
Frontal brain:
Behavior
Abstract thought processes
Problem solving
Attention
Creative thought
Some emotion
Intellect
Reflection
Judgment
Initiative
Inhibition
Coordination of movements
Generalized and mass movements
Some eye movements
Sense of smell
Muscle movements
Skilled movements
Some motor skills
Physical reaction
Parietal lobe
Sense of touch (tactile senstation)
Appreciation of form through touch (stereognosis)
Response to internal stimuli (proprioception)
Sensory combination and comprehension
Some language and reading functions
Some visual functions
Temporal lobe
Auditory memories
Some hearing
Visual memories
Some vision pathways
Other memory
Music
Fear
Some language
Some speech
Some behavior amd emotions
Sense of identity
Occipital lobe

Vision
Reading
Cerebellum:
Balance
Posture
Cardiac, respiratory, and vasomotor centers
The brain stem:
Motor and sensory pathway to body and face
Vital centers: cardiac, respiratory, vasomotor
Neurons in the brain:
Proteins in the brain:tau
Tau protein is a highly soluble microtubuleassociated protein (MAP). In humans, these
proteins are mostly found in neurons compared to
non-neuronal cells. One of tau's main functions is to
modulate the stability of axonal microtubules.
Other nervous system MAPs may perform similar
functions, as suggested by tau knockout mice, who
did not show abnormalities in brain development possibly because of compensation in tau deficiency
by other MAPs.
Tau is not present in dendrites and is active primarily in the distal portions of
axons where it provides microtubule stabilization but also flexibility as
needed. This contrasts with MAP6 (STOP) proteins in the proximal portions of
axons which essentially lock down the microtubules and MAP2 that stabilizes
microtubules in dendrites.
Tau proteins interact with tubulin to stabilize microtubules and promote
tubulin assembly into microtubules. Tau has two ways of controlling
microtubule stability: isoforms and phosphorylation.
Six tau isoforms exist in human brain tissue, and they are distinguished by
their number of binding domains. Three isoforms have three binding domains
and the other three have four binding domains. The binding domains are
located in the carboxy-terminus of the protein and are positively-charged
(allowing it to bind to the negatively-charged microtubule). The isoforms with
four binding domains are better at stabilizing microtubules than those with
three binding domains. The isoforms are a result of alternative splicing in
exons 2, 3, and 10 of the tau gene.
Tau is a phosphoprotein with 79 potential Serine (Ser) and Threonine (Thr)
phosphorylation sites on the longest tau isoform. Phosphorylation has been
reported on approximately 30 of these sites in normal tau proteins.
Phosphorylation of tau is regulated by a host of kinases, including PKN, a
serine/threonine kinase. When PKN is activated, it phosphorylates tau,
resulting in disruption of microtubule organization.
Phosphorylation of tau is also developmentally regulated. For example, fetal
tau is more highly phosphorylated in the embryonic CNS than adult tau.[8]
The degree of phosphorylation in all six isoforms decreases with age due to
the activation of phosphatases.
Hyperphosphorylation of the tau protein (tau inclusions, pTau) can result in
the self-assembly of tangles of paired helical filaments and straight
filaments, which are involved in the pathogenesis of Alzheimer's disease
and other tauopathies.
All of the six tau isoforms are present in an often
hyperphosphorylated state in paired helical filaments
from Alzheimer's disease brain. In other
neurodegenerative diseases, the deposition of
aggregates enriched in certain tau isoforms has been
reported. When misfolded, this otherwise very soluble
protein can form extremely insoluble aggregates that
contribute to a number of neurodegenerative diseases.
Alzheimer's disease
Normal function of APP
Amyloid precursor protein (APP) is an integral
membrane protein expressed in many tissues and
concentrated in the synapses of neurons. Its
primary function is not known, though it has been
implicated as a regulator of synapse formation,[3]
neural plasticity[4] and iron export.[5] APP is best
known as the precursor molecule whose
proteolysis generates beta amyloid (Aβ), a 37 to 49
amino acid peptide whose amyloid fibrillar form is
the primary component of amyloid plaques found
in the brains of Alzheimer's disease patients.
APP is an ancient and highly conserved protein In humans, the gene for APP is
located on chromosome 21 and contains at least 18 exons in 240
kilobases.Several alternative splicing isoforms of APP have been observed in
humans, ranging in length from 365 to 770 amino acids, with certain isoforms
preferentially expressed in neurons; changes in the neuronal ratio of these
isoforms have been associated with Alzheimer's disease.[9] Homologous
proteins have been identified in other organisms such as Drosophila (fruit
flies), C. elegans (roundworms), and all mammals.The amyloid beta region of
the protein, located in the membrane-spanning domain, is not well conserved
across species and has no obvious connection with APP's native-state
biological functions.
Mutations in critical regions of Amyloid Precursor Protein, including the
region that generates amyloid beta (Aβ), cause familial susceptibility to
Alzheimer's disease.For example, several mutations outside the Aβ region
associated with familial Alzheimer's have been found to dramatically increase
production of Aβ.*14]
A mutation (A673T) in the APP gene protects against Alzheimer’s disease. This
substitution is adjacent to the beta secretase cleavage site and results in a
40% reduction in the formation of amyloid beta in vitro.
#amyloid protein in the brain
. In Alzheimer’s disease (AD), amyloid fibrils are formed from Aβ peptide. This
peptide is produced at cholesterol-rich regions of neuronal membranes and
secreted into the extracellular space. Aβ peptide can vary in length. The 40residue peptide Aβ(1–40) represents the most abundant Aβ species in normal
and AD brains, followed by the 42-residue peptide Aβ(1–42). Aβ(1–40) and
Aβ(1–42) are able to adopt many differently shaped aggregates including
amyloid fibrils as well as nonfibrillar aggregates that are sometimes termed
also Aβ “oligomers” .It is not well established which Aβ state is most
responsible for AD or why. Nor exists consensus on the precise subcellular
location of Aβ pathogenicity. Aβ peptide and Aβ amyloid plaques typically
occur outside the cell
Mechanism of amyloid beta:

accumulation of heterogeneous aggregated APP fragments and Abeta appears to
mimic the pathophysiologyof dystrophic neurites, where the same spectrum of
components has been identified by immunohistochemistry. In the brain, this residue
appears to be released into the extracellular space, possibly by a partially apoptotic
mechanism that is restricted to the distal compartments of the neuron. Ultimately,
this insoluble residue may be further digested to the protease-resistant A(beta)n-42
core, perhaps by microglia, where it accumulates as senile plaques. Thus, the
dystrophic neurites are likely to be the source of the immediate precursors of
amyloid in the senile plaques. This is the opposite of the commonly held view that
extracellular accumulation of amyloid induces dystrophic neurites. Many of the key
pathological events of AD may also be directly related to the intracellular
accumulation of this insoluble amyloid. The aggregated, intracellular amyloid
induces the production of reactive oxygen species (ROS) and lipid peroxidation
products and ultimately results in the leakage of the lysosomal membrane. The
breakdown of the lysosomal membrane may be a key pathogenic event, leading to
the release of heparan sulfate and lysosomal hydrolases into the cytosol.
Result (accumulation of beta
amyloid)
AD pathogenesis is believed to be triggered by the
accumulation of the amyloid-β peptide (Aβ), which
is due to overproduction of Aβ and/or the failure
of clearance mechanisms. Aβ self-aggregates into
oligomers, which can be of various sizes, and forms
diffuse and neuritic plaques in the parenchyma
and blood vessels. Aβ oligomers and plaques are
potent synaptotoxins, block proteasome
function, inhibit mitochondrial activity, alter
intracellular Ca2+ levels and stimulate
Loss of the normal physiological functions of Aβ is also thought
to contribute to neuronal dysfunction. Aβ interacts with the
signalling pathways that regulate the phosphorylation of the
microtubule-associated protein tau. Hyperphosphorylation of
tau disrupts its normal function in regulating axonal transport
and leads to the accumulation of neurofibrillary tangles and toxic
species of soluble tau. Furthermore, degradation of
hyperphosphorylated tau by the proteasome is inhibited by the
actions of Aβ. These two proteins and their associated signalling
pathways therefore represent important therapeutic targets for
AD.
Genes and beta amyloid
Abeta is generated by proteolytic processing of the betaamyloid precursor protein (betaAPP) involving the
combined action of beta- and gamma-secretase.
Cleavage within the Abeta domain by alpha-secretase
prevents Abeta generation. In some very rare cases of
familial AD (FAD), mutations have been identified within
the betaAPP gene. These mutations are located close to
or at the cleavage sites of the secretases and
pathologically effect betaAPP processing by increasing
Abeta production,
References:
http://www.nature.com/nrn/posters/ad/index.ht
ml
http://www.ncbi.nlm.nih.gov/pubmed/10653281
http://en.wikipedia.org/wiki/Amyloid_precursor_
protein
http://en.wikipedia.org/wiki/Amyloid_precursor_
protein

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Alzheimer's disease

  • 2. The content: Structure of the brain Important proteins in our brain Alzheimer’s disease
  • 3. Structure of the brain: Cerebrum and cerebellum Cerebrum: Frontal lobe Parietal lobe Temporal lobe Occipital lobe >>>>>>>>>> Brain stem
  • 4. Frontal brain: Behavior Abstract thought processes Problem solving Attention Creative thought Some emotion Intellect Reflection Judgment Initiative Inhibition Coordination of movements Generalized and mass movements Some eye movements Sense of smell Muscle movements Skilled movements Some motor skills Physical reaction
  • 5. Parietal lobe Sense of touch (tactile senstation) Appreciation of form through touch (stereognosis) Response to internal stimuli (proprioception) Sensory combination and comprehension Some language and reading functions Some visual functions
  • 6. Temporal lobe Auditory memories Some hearing Visual memories Some vision pathways Other memory Music Fear Some language Some speech Some behavior amd emotions Sense of identity
  • 9. The brain stem: Motor and sensory pathway to body and face Vital centers: cardiac, respiratory, vasomotor
  • 10. Neurons in the brain:
  • 11. Proteins in the brain:tau Tau protein is a highly soluble microtubuleassociated protein (MAP). In humans, these proteins are mostly found in neurons compared to non-neuronal cells. One of tau's main functions is to modulate the stability of axonal microtubules. Other nervous system MAPs may perform similar functions, as suggested by tau knockout mice, who did not show abnormalities in brain development possibly because of compensation in tau deficiency by other MAPs.
  • 12. Tau is not present in dendrites and is active primarily in the distal portions of axons where it provides microtubule stabilization but also flexibility as needed. This contrasts with MAP6 (STOP) proteins in the proximal portions of axons which essentially lock down the microtubules and MAP2 that stabilizes microtubules in dendrites. Tau proteins interact with tubulin to stabilize microtubules and promote tubulin assembly into microtubules. Tau has two ways of controlling microtubule stability: isoforms and phosphorylation.
  • 13. Six tau isoforms exist in human brain tissue, and they are distinguished by their number of binding domains. Three isoforms have three binding domains and the other three have four binding domains. The binding domains are located in the carboxy-terminus of the protein and are positively-charged (allowing it to bind to the negatively-charged microtubule). The isoforms with four binding domains are better at stabilizing microtubules than those with three binding domains. The isoforms are a result of alternative splicing in exons 2, 3, and 10 of the tau gene.
  • 14. Tau is a phosphoprotein with 79 potential Serine (Ser) and Threonine (Thr) phosphorylation sites on the longest tau isoform. Phosphorylation has been reported on approximately 30 of these sites in normal tau proteins. Phosphorylation of tau is regulated by a host of kinases, including PKN, a serine/threonine kinase. When PKN is activated, it phosphorylates tau, resulting in disruption of microtubule organization.
  • 15. Phosphorylation of tau is also developmentally regulated. For example, fetal tau is more highly phosphorylated in the embryonic CNS than adult tau.[8] The degree of phosphorylation in all six isoforms decreases with age due to the activation of phosphatases.
  • 16. Hyperphosphorylation of the tau protein (tau inclusions, pTau) can result in the self-assembly of tangles of paired helical filaments and straight filaments, which are involved in the pathogenesis of Alzheimer's disease and other tauopathies.
  • 17. All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments from Alzheimer's disease brain. In other neurodegenerative diseases, the deposition of aggregates enriched in certain tau isoforms has been reported. When misfolded, this otherwise very soluble protein can form extremely insoluble aggregates that contribute to a number of neurodegenerative diseases.
  • 19. Normal function of APP Amyloid precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation,[3] neural plasticity[4] and iron export.[5] APP is best known as the precursor molecule whose proteolysis generates beta amyloid (Aβ), a 37 to 49 amino acid peptide whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients.
  • 20. APP is an ancient and highly conserved protein In humans, the gene for APP is located on chromosome 21 and contains at least 18 exons in 240 kilobases.Several alternative splicing isoforms of APP have been observed in humans, ranging in length from 365 to 770 amino acids, with certain isoforms preferentially expressed in neurons; changes in the neuronal ratio of these isoforms have been associated with Alzheimer's disease.[9] Homologous proteins have been identified in other organisms such as Drosophila (fruit flies), C. elegans (roundworms), and all mammals.The amyloid beta region of the protein, located in the membrane-spanning domain, is not well conserved across species and has no obvious connection with APP's native-state biological functions. Mutations in critical regions of Amyloid Precursor Protein, including the region that generates amyloid beta (Aβ), cause familial susceptibility to Alzheimer's disease.For example, several mutations outside the Aβ region associated with familial Alzheimer's have been found to dramatically increase production of Aβ.*14] A mutation (A673T) in the APP gene protects against Alzheimer’s disease. This substitution is adjacent to the beta secretase cleavage site and results in a 40% reduction in the formation of amyloid beta in vitro.
  • 21. #amyloid protein in the brain . In Alzheimer’s disease (AD), amyloid fibrils are formed from Aβ peptide. This peptide is produced at cholesterol-rich regions of neuronal membranes and secreted into the extracellular space. Aβ peptide can vary in length. The 40residue peptide Aβ(1–40) represents the most abundant Aβ species in normal and AD brains, followed by the 42-residue peptide Aβ(1–42). Aβ(1–40) and Aβ(1–42) are able to adopt many differently shaped aggregates including amyloid fibrils as well as nonfibrillar aggregates that are sometimes termed also Aβ “oligomers” .It is not well established which Aβ state is most responsible for AD or why. Nor exists consensus on the precise subcellular location of Aβ pathogenicity. Aβ peptide and Aβ amyloid plaques typically occur outside the cell
  • 22. Mechanism of amyloid beta: accumulation of heterogeneous aggregated APP fragments and Abeta appears to mimic the pathophysiologyof dystrophic neurites, where the same spectrum of components has been identified by immunohistochemistry. In the brain, this residue appears to be released into the extracellular space, possibly by a partially apoptotic mechanism that is restricted to the distal compartments of the neuron. Ultimately, this insoluble residue may be further digested to the protease-resistant A(beta)n-42 core, perhaps by microglia, where it accumulates as senile plaques. Thus, the dystrophic neurites are likely to be the source of the immediate precursors of amyloid in the senile plaques. This is the opposite of the commonly held view that extracellular accumulation of amyloid induces dystrophic neurites. Many of the key pathological events of AD may also be directly related to the intracellular accumulation of this insoluble amyloid. The aggregated, intracellular amyloid induces the production of reactive oxygen species (ROS) and lipid peroxidation products and ultimately results in the leakage of the lysosomal membrane. The breakdown of the lysosomal membrane may be a key pathogenic event, leading to the release of heparan sulfate and lysosomal hydrolases into the cytosol.
  • 23. Result (accumulation of beta amyloid) AD pathogenesis is believed to be triggered by the accumulation of the amyloid-β peptide (Aβ), which is due to overproduction of Aβ and/or the failure of clearance mechanisms. Aβ self-aggregates into oligomers, which can be of various sizes, and forms diffuse and neuritic plaques in the parenchyma and blood vessels. Aβ oligomers and plaques are potent synaptotoxins, block proteasome function, inhibit mitochondrial activity, alter intracellular Ca2+ levels and stimulate
  • 24. Loss of the normal physiological functions of Aβ is also thought to contribute to neuronal dysfunction. Aβ interacts with the signalling pathways that regulate the phosphorylation of the microtubule-associated protein tau. Hyperphosphorylation of tau disrupts its normal function in regulating axonal transport and leads to the accumulation of neurofibrillary tangles and toxic species of soluble tau. Furthermore, degradation of hyperphosphorylated tau by the proteasome is inhibited by the actions of Aβ. These two proteins and their associated signalling pathways therefore represent important therapeutic targets for AD.
  • 25. Genes and beta amyloid Abeta is generated by proteolytic processing of the betaamyloid precursor protein (betaAPP) involving the combined action of beta- and gamma-secretase. Cleavage within the Abeta domain by alpha-secretase prevents Abeta generation. In some very rare cases of familial AD (FAD), mutations have been identified within the betaAPP gene. These mutations are located close to or at the cleavage sites of the secretases and pathologically effect betaAPP processing by increasing Abeta production,