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1. Alzheimer's disease

2. • Alzheimer's Disease (AD) is the leading cause
of dementia in the elderly and is the fourth
leading cause of death in developed nations
(after heart disease, cancer, and stroke),
although AD victims tend to actually die of
infection secondary to AD.
• AD affects roughly 2% of those 65 years of age,
with the incidence roughly doubling every 5 years
up to age 90 at which the incidence is over 50%.
• AD is much more prevalent in women than in
men for any given age group.

3. THE AMYLOID CASCADE HYPOTHESIS
• The molecular mechanisms and hypotheses of Alzheimer's
Disease (AD) can be incredibly complex.
• The key event leading to AD appears to be the formation of
a peptide (protein) known as amyloid beta (beta amyloid,
Aß) which clusters into amyloid plaques (senile plaques) on
the blood vessels and on the outside surface of neurons of
the brain (amyloidosis) — which ultimately leads to the
killing of neurons.

4. • Aß formation ⇒ amyloid
plaques ⇒ neuron death ⇒ dementia

5. • Amyloid beta peptide is created by enzyme clipping of the normal neuron
membrane protein known as Amyloid Precursor Protein (APP).
• APP is actually thought to be a natural neuroprotective agent induced by
neuronal stress or injury, which reduces Ca2+ concentration and protects
neurons from glutamate excitotoxicity
• Enzymes can clip APP in ways that do not result in amyloid beta
formation. Moreover, there are two forms of amyloid beta peptide, one of
which has 40 amino acids and one of which has 42 amino acids.

6. • The enzymes that cleave APP are known as secretases. The two enzymes
that initially compete to cleave APP are alpha-secretase (α-secretase) and
beta-secretase (β-secretase, BACE1).
• If alpha-secretase cleaves APP there is no formation of Aß.
• If APP is cleaved by beta-secretase it can then be further cleaved by
gamma-secretase (γ-secretase) to form either a 40 amino acid amyloid
peptide (Aß40) which is soluble & mostly innocuous — or a 42 amino acid
peptide (Aß42) which clumps together to form insoluble amyloid plaques.
• Alpha-secretase cleavage occurs at the cell surface, whereas beta-secretase
acts at the endoplasmic reticulum. Gamma-secretase produces Aß42 if
cleavage occurs in the endoplasmic reticulum and Aß40 if the cleavage is
in the trans-Golgi network
• The 42 amino acid amyloid beta peptide (Aß42) is more hydrophobic &
"sticky" (and hence aggregates more readily) than the 40 amino acid
amyloid beta peptide (Aß40).

9. With these facts in mind, the second sketch of the amyloid cascade would be:
APP ⇒ Aß42 ⇒ fibrillar Aß and oligomers ⇒ amyloid plaques
amyloid plaques ⇒ inflammation and NFTs ⇒ neuron death and synapse loss

10. • GENETIC DETERMINANTS OF
ALZHEIMER'S DISEASE

11. • Alzheimer's Disease (AD) can be divided into forms that run in families (genetically
inherited) [known as Familial Alzheimer's Disease (FAD)] and forms showing no
clear inheritance pattern [known as Sporadic Alzheimer's Disease (SAD)]. FAD
accounts for only a small portion (less than 10%) of AD. All FAD is early-onset —
usually occurring between ages 30 to 60 — whereas SAD typically occurs after age
65.
• All FADs can be cited as evidence of the amyloid cascade interpretation of AD
causation — against the suggestion that NeuroFibrillary Tangles (NFTs), inflammation,
or oxidative stress initiate AD (in FAD, at least).
• The gene that encodes tau-protein is located on chromosome 17 and is not
associated with any FAD. In fact, at least half of FAD cases can be accounted for by
the PS1 (Pre-Senilin 1) gene located on chromosome 14.
• PS1 is the predominant enzyme cleaving the gamma-secretase site. PS1 resides
within the endoplasmic reticulum/Golgi complex. Abnormal proteins from the PS1 and
PS2 genes apparently influence gamma-secretase enzyme causing more Aß42
peptide formation.
• The mutation on chromosome 21 (the chromosome that is present in triplicate in
Down's Syndrome) is on the Amyloid Precursor Protein (APP) gene itself, resulting
in abnormal APP protein that is preferentially cleaved by secretases to form more
Aß42. (Down's Syndrome victims frequently develop AD if they reach age 40.)

13. TAU PROTEIN AND NEUROFIBRILLARY
TANGLES (NFTs)

14. • Tau is a protein that stabilizes the skeletal scaffoding of neurons, ie, a
protein that stabilizes the cytoskeletal microtubules. Tau is mainly present in
the axons of neurons. A single gene on human chromosome 17 results in
the production of five tau protein isoforms in the adult CNS, the longest of
which contains 441 residues (ie, 441 amino acids). A number of kinases
can phosphorylate (add a phosphate to) tau and a few phosphatases can
dephosphorylate tau.
• The phosphorylation state of tau affects the protein's ability to self-associate
or bind microtubules. Heat shock proteins and the chaperone protein Pin1
can also affect tau properties. The pathological isoforms of tau in Pick's
disease and frontotemporal dementia are distinctive from those of
Alzheimer's Disease, but the pattern in Down's Syndrome (trisomy of
chromosome 21) is very similar to that seen in AD
• in the association areas of the cerebral cortex, whereas NeuroFibrillary
Tangles (NFTs, also called Paired Helical Filaments, PHFs) typically begin
in the entorhinal cortex.

18. Parkinson’s disease

19. Parkinson’s disease
• a progressive disease of the nervous system
marked by tremor, muscular rigidity, and
slow, imprecise movement, chiefly affecting
middle-aged and elderly people.
• It is associated with degeneration of the basal
ganglia of the brain and a deficiency of the
neurotransmitter dopamine.

20. Parkinson’s disease
→2nd most common neurodegenerative disease due to
aging
→Degeneration of specific dopaminergic neurons in the
substantia nigra
→Accumulation of α-synuclein protein in presence of
dopamine
→Other neurons are not affected
Α-synuclein accumulating neurons

22. Parkinson’s disease
Resulting symptoms
• Muscular rigidity → extreme pain
• Postural instability
• Resting tremor

23. • When L-dopa or dopamine is not biosynthesized
properly in the dopaminergic neurons, as occurs in
Parkinson's Disease, certain cytological effects can
occur.
• This can result in the formation of Superoxide anion,
Neuromelanin formation, Iron accumulation, the
accumulation of Alpha-synuclein, and the formation of
Lewy bodies.

24. • Often at the Science of Parkinson’s disease,
we will discuss something called ‘Alpha
Synuclein’.

25. • Proteins make up the many pieces of machinery inside
each cell that makes our brains work. In order for each
protein to function properly, they must be folded into the
correct shape when they are first made.
• Alpha synuclein is extremely abundant in our brains –
making up about 1% of all the proteins floating around in
each neuron (one of the main types of cell in the brain).
• In healthy brain cells, correctly constructed alpha
synuclein is typically found just inside the surface of
membrane surrounding the cell body and in the tips of
the branches extending from the cells

26. • So why is alpha synuclein important in
Parkinson’s disease?
• Genetic mutations account for 10-20% of
the cases in Parkinson’s disease.
• Five mutations in the alpha-synuclein gene
have been identified which are associated
with increased risk of Parkinson’s disease
(A53T, A30P, E46K, H50Q, and G51D –
these are coordinates for locations on the
alpha synuclein gene).

28. What are Lewy bodies?
• Lewy bodies are circular clumps of alpha
synuclein (and other proteins) that are
found in the brains of people with
Parkinson’s disease.
• They are very abundant in areas of the
brain that have suffered cell loss, such as
the region containing dopamine neurons.

30. Superoxide anion
• The first step in the formation of dopamine is the
biosynthesis of L-dopa from L-tyrosine. In Parkinson's
Disease, largely due to inadequate cofactors, L-tyrosine
and molecular oxygen do not completely form L-dopa.
• Consequently, the toxic partial reduction product of
oxygen, the superoxide anion can be formed instead.
Superoxide (O2-) is formed by the oxidation of ferrous
ions (Fe2+) by dioxygen (O2).

31. • Neuromelanin
• When L-Dopa is unable to form dopamine it may instead lead to the
formation and accumulation of neuromelanin, which is similar to the
pigment melanin found in skin. It can do this via the enzyme
peroxidase instead of the enzyme tyrosinase, which is usually
responsible for melanin production, because tyrosinase does not
occur in the dopaminergic neurons.

33. • Iron accumulation
• Iron is essential for the formation of L-dopa. So the deficiency of iron
can cause insufficient L-dopa. Insufficient formation of L-dopa is the
primary biochemical fault in Parkinson's Disease. It is a common
compensatory mechanism in biochemistry for a cofactor such as
ferrous iron to accumulate when the substance it facilitates the
formation of is deficient. That is why instead of iron accumulation
causing Parkinson's Disease, Parkinson's Disease can cause an
accumulation of iron.

35. • Alpha-synuclein
• Iron accumulation also increases the aggregation of alpha-synuclein. Alpha-synuclein
expression is regulated by iron mainly at the translational level. The superoxide anion
can also be produced as a result of Parkinson's Disease when L-dopa is formed
insufficiently. Superoxide is broken down to hydrogen peroxide (H2O2) by the
enzyme Superoxide Dismutase. Hydrogen peroxide (H2O2) plays a dominant role in
the aggregation of alpha-synuclein. So it is Parkinson's Disease, due to insufficient
formation of L-dopa, that causes the aggregation of alpha-synuclein.
• Lewy bodies
• Lewy bodies are characterised by abnormal intraneuronal deposits (Lewy bodies) and
intraneuritic deposits (Lewy neurites) of fibrillary aggregates and Lewy grains.
Aggregated alpha-synuclein is the major component of Lewy bodies, Lewy neurites
and Lewy grains and the primary cause of Lewy body formation. The deposits of
alpha-synuclein in Lewy bodies colocalize with ubiquitin, which is the second major
component of Lewy bodies.

36. Huntington's disease
• Huntington disease is a progressive
brain disorder that causes uncontrolled
movements, emotional problems, and loss
of thinking ability (cognition).
• Adult-onset Huntington disease, the
most common form of this disorder,
usually appears in a person's thirties or
forties.

37. Huntington’s disease
• Polyglutamine disease → mutation encoding for an
addition of amino-acids
• Accumulation of the misfolded protein Huntingtin
• Formation of toxic inclusions in brain cells
• Degeneration of glutamatergic striatal neurons
polyQ inclusion
In neocortex

39. • There are multiple cellular changes through which the toxic function of
mHTT may manifest and produce the HD pathology.
• In its mutant (i.e. polyglutamine expanded) form, the protein is more
prone to cleavage that creates shorter fragments containing the
polyglutamine expansion.
• These protein fragments have a propensity to undergo misfolding and
aggregation, yielding fibrillar aggregates in which non-native
polyglutamine β-strands from multiple proteins are bonded together via
hydrogen bonds.[
• These aggregates share the same fundamental cross-β amyloid
architecture seen in other protein deposition diseases. Over time, the
aggregates accumulate to form inclusion bodies within cells, ultimately
interfering with neuron function.

40. • Several pathways by which mHTT may cause
cell death have been identified.
• These include: effects on chaperone proteins,
which help fold proteins and remove misfolded
ones; interactions with caspases, which play a
role in the process of removing cells; the toxic
effects of glutamine on nerve cells; impairment
of energy production within cells; and effects on
the expression of genes.

41. • Excitotoxicity is the pathological process by which nerve cells are
damaged or killed by excessive stimulation by neurotransmitters such as
glutamate and similar substances.
• This occurs when receptors for the excitatory neurotransmitter glutamate
(glutamate receptors) such as the NMDA receptor and AMPA receptor
are overactivated by glutamatergic storm.
• Excitotoxins like NMDA and kainic acid which bind to these receptors, as
well as pathologically high levels of glutamate, can cause excitotoxicity by
allowing high levels of calcium ions (Ca2+) to enter the cell.
• Ca2+ influx into cells activates a number of enzymes, including
phospholipases, endonucleases, and proteases such as calpain. These
enzymes go on to damage cell structures such as components of the
cytoskeleton, membrane, and DNA.

43. Therapeutic solutions
3 main approaches:
1. Inhibition of protein aggregation
2. Interference with post-translational peptide changes
before the misfolding/aggregation step
3. Upregulation of molecular chaperones or aggregate-
clearance mechanisms

44. Therapeutic solutions
2.
• Targeting Aβ-formation by inhibiting β- and γ- secretase
proteins responsible for the formation of amyloid plaques
• Inhibition of tau protein phosphorylation
(hyperphosphorylation of tau protein is responsible for its
aggregation)

45. Therapeutic solutions
3.
Clonidine and Minoxidil enhance the clearance of
aggregate prone proteins, including mutant
Huntingtin and mutants of α-synuclein