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BoD - Neuro > 18Neuro - Alzheimer's Disease > Flashcards

18Neuro - Alzheimer's Disease Flashcards

1
Q

When and by whom was Alzheimer’s disease discovered?

A

Alzheimer’s Disease was discovered by Alois Alzheimer in 1907.

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2
Q

What is Alzheimer’s disease?

A

Alzheimer’s disease is a form of senile dementia - it is the most common form of neurodegenerative disease of the aging.

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3
Q

What percentage of people have Alzheimer’s disease?

A

7% of over 65s and 20% of over 80s have Alzheimer’s disease.

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4
Q

What percentage of all cases of dementia does Alzheimer’s account for?

A

Alzheimer’s disease accounts for 50% of all cases of dementia.

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5
Q

What sociological challenges does Alzheimer’s disease present?

A

It is becoming an increasing problem with an ageing Western population and there is no cure.

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6
Q

Why is diagnosis of Alzheimer’s disease challenging?

A

Alzheimer’s disease is difficult to definitively diagnose until post-mortem as symptoms could be caused by another form of dementia.

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7
Q

What are the symptoms of Alzheimer’s disease?

A

Progressive deterioration of intellect, memory, language, orientation and personality.

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8
Q

What are the pathological features of Alzheimer’s disease?

A

Pathological features include atrophy of the brain - in particular the hippocampus, areas of the cerebral cortex, olfactory bulb and olfactory complex.
Loss of neurons and appearance of abnormal protein deposits, amyloid plaques and neurofibrillary tangles (NFT).

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9
Q

What are amyloid plaques?

A

Extracellular protein deposits surrounding dystrophic neurites (degenerating neurons). They consist of a core of 6-10nm radiating fibrils. May form in neuron which dies to leave plaque.

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10
Q

What does solubilisation of an amyloid plaque yield?

A

Upon solublisation of an amyloid plaque, a 4 kDa polypeptide known as amyloid beta (A-beta, A4, amyloid P peptide) is obtained.

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11
Q

Are amyloid plaques soluble?

A

Amyloid beta plaques are very difficult to solubilise.

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12
Q

What are neurofibrillary tangles?

A

Neurofibrillary tangles are intracellular deposits of insoluble proteins in neuronal cell bodies. They consist of paired helical fragments (PHFs) of 10nm protein fibres twisted around each other and crossing over every 80nm in a beta-pleated sheet structure. They contain Tau, neurofilament proteins and ubiquitin.

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13
Q

What is Tau?

A

Tau is a protein which stabilises microtubules.

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14
Q

Why is the presence of ubiquitin in a neurofibrillary tangle significant?

A

It may suggest aggresome formation. Aggresomes form when the cell’s protein degradation mechanism become overwhelmed. Ubiquitin is associated with the proteasomal degradation pathway. This is similar to Parkinson’s disease.

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15
Q

What did the sequence of Aβ from plaques permit?

A

The sequence of Aβ from plaques permitted synthesis of oligonucleotide probes and search of human brain cDNA library.

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16
Q

What did the putative sequence of Aβ precursor, Amyloid Precursor Protein (which included an internal sequence identical to Aβ) suggest about the protein?

A

It suggested that it had an N-terminal sequence for membrane insertion and a membrane spanning domain (⅓ of Aβ sequence is in membrane spanning domain). Aβ has to be excised from longer protein.

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17
Q

Which chromosome is the APP gene localised to?

A

The APP gene is localised to Chromosome 21.

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18
Q

What does the APP gene contain?

A

The APP gene has two alternately spliced exons of 56 and 19 amino acids inserted at residue 289; the first contains a serine protease inhibitor domain of the Kunitz type (KPI).

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19
Q

How many possible transcripts are there of the APP gene and what are they?

A

There are 3 possible transcripts:
APP 695 = widespread in both neural and non-neural tissues, NEURONS
APP 751 = 56 residue insert, 50% homologous to the Kunitz serine protease inhibitor, GLIAL CELLS
APP 770 = 56 residue insert + 19 residues
APP751 and 770 proteins processed to release secreted fragment identical to protease inhibitor, “protease nexin II”.

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20
Q

What post-translational modifications is APP subjected to?

A

It is glycosylated and expressed at the cell surface.

It is also processed into fragments.

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21
Q

What is the function of APP 751 and 779 N-terminal secreted fragments?

A

APP751 and 770 N-terminal secreted fragments may complex with extracellular proteases and have growth promoting activities

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22
Q

What are some of the hypothesised functions of APP?

A

It may play a role in neuronal migration due to synaptic connection. It may be involved in signalling via G0. Ser/Thr residues may be phosphorylated indicating that it may be a modulator of signalling.

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23
Q

What are some of the roles the C-terminal APP Intracellular Domain (AICD) believed to have?

A

It may be involved in calcium homeostasis. It also regulates lipoprotein receptor protein 1 expression and therefore ApoE expression and cholesterol metabolism.

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24
Q

What role may amyloid beta have in neurones?

A

Amyloid β may have role in synaptic plasticity.

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25
Q

What evidence is there linking APP and Aβ with Alzheimer’s disease?

A

Abnormal deposits of Aβ which is derived from APP accumulate in AD brains.
Mutations in APP gene co-segregate with the disease in some cases of familial AD (FAD).
Down’s Syndrome = suffer from early Alzheimer’s Disease, together with amyloid plaques, chromosome 21 trisomy = APP gene dosage effect?
Higher levels of Aβ = early onset of AD

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26
Q

What must happen to APP to yield Aβ?

A

APP must be proteolytically processed in order to yield Aβ.

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27
Q

What different forms is Aβ found in?

A

Aβ is found in different forms; 39/40 and 42 amino acids long.

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28
Q

Which form of Aβ is most prone to plaque formation?

A

The 42 amino acid long peptide is a major factor in plaque formation.

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29
Q

There is evidence for alternate pathways of APP processing; what are these pathways?

A

The two pathways of APP processing are the amyloidogenic pathway (which generates Aβ) and the non-amyloidogenic pathway (which does not generate Aβ). The balance between the two pathways is essential in determining whether Alzheimer’s Disease will develop.

30
Q

What are the features of the non-amyloidogenic pathway of APP processing?

A

Non-amyloidogenic processing of APP:
α-secretase/ADAM 10 (metalloproteinase in plasma membrane) cleaves between residues 16-17 of Aβ domain
N-terminal fragment secreted (sAPPα)
C-terminal fragment (C83, “αstub”) cleaved by γ-secretase to release small fragment from Aβ domain (p3), remainder internalised and degraded in endosome/lysosome system (α-CTF)

31
Q

What are the features of the amyloidogenic pathway of APP processing?

A

Amyloidogenic processing of APP:
β-secretase (BACE) cleaves APP at N-terminus of Aβ domain to generate intracellular C99 (“βstub”) and soluble APPsβ (secreted)
C99 cleaved by ε-secretase and γ-secretase to generate soluble intracellular AICD and Aβ containing fragment
Site of cleavage by γ-secretase crucial for amyloidogenesis: Aβ42 more fibrillogenic than Aβ40

32
Q

How is most APP processed?

A

Most APP is processed via the non-amyloidogenic pathway.

33
Q

If the non-amyloidogenic pathway is the major pathway of APP processing - when does the amyloidogenic pathway occur?

A

The amyloidogenic pathway is generating small amounts of Aβ constitutively, this results in slow accumulation of Aβ with age. Amyloid deposits are normal in aged brains. However, in Alzheimer’s disease the accumulation of Aβ is considerably accelerated.

34
Q

What can make production of Aβ more likely?

A

Mutations in APP or secretases promote alternate processing to yield Aβ.

35
Q

What are the reasons for increased amyloidogenic processing in sporadic cases of Alzheimer’s disease and familial forms of the disease?

A

The reasons for increased amyloidogenic processing of APP are unclear in cases of sporadic Alzheimer’s disease (the most common form). However, a number of mutations have been identified in the APP gene which segregate in Familial Alzheimer’s disease (FAD).

36
Q

What are the differences or similarities between sporadic and familial forms of Alzheimer’s disease in terms of their pathology and the onset of symptoms?

A

The pathology of sporadic and familial forms of Alzheimer’s disease are identical. However, familial AD has an early onset of symptoms compared to the sporadic form. (It is still age-related though).

37
Q

What are some of the mutations associated with familial Alzheimer’s disease and where are they typically found on the gene?

A

Mutations associated with familial Alzheimer’s disease are typically found close to potential cleavage sites to generate Aβ. For example:
“Swedish” - mutation adjacent to met-asp which must be cleaved to yield Aβ N-terminus
Glu to Gln at residue 22 of Aβ in hereditary Cerebral Haemorrhage with Amyloidosis - Dutch type
Mutations at 717, downstream of Aβ

38
Q

What is about larger Aβ particles that make them problematic?

A

Larger Aβ particles are more likely to adopt β-pleated sheet rather than alpha-helix and form fibrils in vitro. In addition, Aβ 42/3 particles are more fibrillogenic than smaller fragments and seed plaques which promote Aβ40 accumulation.

39
Q

In normal individuals, what type of Aβ fragments predominate?

A

In normal individuals, Aβ fragments of less than 40 amino acids long predominate.

40
Q

What may promote aggregation and insolubility of Aβ particles?

A

The concentration of Aβ in the endosome/lysosome system may promote aggregation and insolubility.

41
Q

Why does amyloid lead to cell death?

A

Toxic gain of function.

42
Q

What are some of the effects of the neurotoxic Aβ soluble oligomers?

A

Promote hyperphosphorylation of tau by Glycogen Synthase Kinase-3 (GSK-3) and tangle formation
Form pores in cell membrane and may allow Ca2+ entry, free radical production and apoptosis
Activate various cell surface receptors leading to cell death
Inhibit the UPS, ERAD and autophagy
Accumulation of insoluble Aβ plaques may damage cell structure and lead to cell death (late events)
May activate glial cells and neuro-inflammatory (leading to ROS)

43
Q

Why are Pre-Senilins considered to be significant in Familial Alzheimer’s disease?

A

In 70-80% of FAD families, the disease co-segregates with chromosome 21 (Pre-senilin) not chromosome 14 (APP) and is associated with early onset of Alzheimer’s disease.

44
Q

What are some of the features of Pre-senalin 1 (PS1)?

A

PS1 has multiple membrane spanning domains and “aspartate protease” activity.

45
Q

What evidence is there that Pre-senilin is involved in Alzheimer’s disease?

A

Cells from patients expressing a mutant form of PS1 generate high levels of Aβ.

46
Q

What causes familial Alzheimer’s disease in Volga Germans?

A

In Volga Germans, FAD is linked to Chromosome 1 and the genes which code for Pre-senilin 2. This protein is similar to Pre-senilin 1.

47
Q

What family of enzymes do pre-senilins belong to?

A

Pre-senilins are part of gamma-secretase family of enzymes. They contain a gamma-secretase active site.

48
Q

What is the link between apolipoprotien E (ApoE) and Alzheimer’s disease?

A

The E4 variant of the ApoE confers a higher risk of developing late onset Alzheimer’s disease. There are three variant of the ApoE protein: E2, E3 and E4. One or two copies of E4 increase risk of AD by 3-12x vs E3. The rare E2 is protective. The Apo E4 associates with Aβ in vitro and promotes fibril formation. It also seems to have a negative effect on Aβ clearance. The stressed cleaves ApoE which increases amyloid β.

49
Q

What is the link between Sortilin-related Receptor 1 and Alzheimer’s disease?

A

Polymorphisms in SORL 1 associated with increased risk of AD (late onset):
Associates with APP and regulates trafficking to and from Golgi (sorting receptor) and therefore processing.
Promotes non-amyloidogenic processing.
Some polymorphisms loose this function .
Also binds LDL, may have an effect on ApoE.
Precise mechanisms of interconnections not fully understood.

50
Q

What other proteins are associated with amyloid β?

A

Plaques also contain a fragment of α-synuclein (Non-Amyloid Component, NAC).
α-synuclein has tendency to form β-sheet and aggregate.
Mutations in α-synuclein associated with familial Parkinson’s Disease.
Plaques also contain complement proteins.

51
Q

How is tau related to neurofibrillary tangles?

A

The micro-tubule protein tau is present in neurofibrillary tangles; may form core of neurofibrillary tangles.

52
Q

What types of abnormal post-translational modifcations does the tau found in neurofibrillary tangles have?

A

Tau found in NFTs appears to be abnormally phosphorylated and may be ubiquitinated.

53
Q

How is tau normally phosphorylated?

A

Normally, Tau is phosphorylated on 3 sites, serine and threonine residues adjacent to proline.

54
Q

Which kinases are suspected to be involved in abnormal phosphorylation of tau?

A

Candidate kinases include MAP kinase, glycogen synthase kinase-3 and proline directed protein kinase.

55
Q

How does tau stabilise the microtubules?

A

Binding of tau to tubulin appears to stabilise the microtubules.

56
Q

What does normal phosphorylation of tau do?

A

Phosphorylation of tau detaches it from the microtubules to allow movement of vesicles.

57
Q

What effect may abnormal phosphorylation have on tau?

A

Abnormal phosphorylation may impair tau binding and destabilise the microtubules and therefore impair axonal transport.

58
Q

What problem may soluble tau pose?

A

Soluble tau may be neurotoxic.

59
Q

How do neurofibrillary tangles correlate with the progression of Alzheimer’s disease?

A

NFTs correlate with the progression of Alzheimer’s disease better than plaques.
Some suggest tau abnormalities crucial to AD.
Suggested that tangles are a consequence of Aβ.
Aβ may activate GSK3/other kinases which may hyperphosphorylate tau.
Tau modification may be key to neuronal loss.

60
Q

In what other diseases are abnormal tau deposits seen?

A

Abnormal tau deposits are also seen in tauopathies such as Frontotemporal Dementia.

61
Q

How are free radicals connected to Alzheimer’s disease?

A

Possible free radical connection to AD suggested:
Iron concentration increased in NFT-bearing neurons - Fenton reaction.
Aβ forms ion pores in cell membrane leading to elevated intracellular Ca2+.
Aβ increases O2.- production in blood vessels, reacts with NO., vasoconstriction.
APP in AD found “stuck” in mitochondrial import machinery, ETC components not imported, electron leakage = ROS formation.

62
Q

What causes apoptosis in Alzheimer’s disease?

A

Apoptosis:
APP appears to have signalling role
Mutant APP may initiate cell division via G0 p21 activated kinase 3 (PAK3) and APP Binding Protein 1 (BP-1)
Hyperphosphorylation of tau during mitosis (Cdk5?)
Neuronal cells not mitosis capable, apoptosis triggered
C-terminal fragments of APP may also trigger apoptosis

63
Q

How is neuroinflammation linked to Alzheimer’s disease?

A

CNS contains microglia immune cells activated by stress (e.g. aggregated proteins)
Phagocytic activity
Release pro-inflammatory mediators
Stimulate formation of ROS and RNS
Aβ activates microglia but prevents phagocytosis of Aβ - amyloid accumulation

64
Q

How is the complement cascade linked to Alzheimer’s disease?

A

The complement cascade is activated by infection/stress:
Leads to (foreign) cell lysis
APP/Aβ appear to upregulate
APP/PSEN mutations lead to increase in Aβ and complement activation
Genome-wide association studies link polymorphisms in complement cascade factors and late onset AD

65
Q

What is the link between vascular events and Alzheimer’s disease?

A

Epidemiological link between vascular damage and AD.
Vascular damage can trigger complement cascade .
Could lead to neuronal cell death and AD in individuals with APP/PSEN mutations (early onset) and complement cascade polymorphisms (late onset).
Feedback on system further stimulates AD progression.

66
Q

What is the link between Alzheimer’s disease and diabetes?

A

Type 2 diabetes increases risk of AD
Insulin Degrading Enzyme (IDE) also degrades Aβ
High levels of insulin, less IDE activity to degrade Aβ
Hyperglycaemia leads to ROS and Advanced Glycation End products (AGE) - contribute to AD pathology
Insulin resistance in brain may contribute to AD
Proposed that AD is “Type 3 diabetes”

67
Q

What are some of the current treatment options?

A

Anti-cholinesterases
Inhibit acetylcholine breakdown e.g. Aricept
Help with memory loss in moderate stage AD
Vaccines
To amyloid peptide antigen, evidence for beneficial effects, trial stopped due to meningoencephalitis
Statins
Lower cholesterol, may reduce isoprenylation of signalling proteins
Some studies indicate statins (simvastatin) lower risk, other studies show no effect

68
Q

What are some of the new therapies specifically targeting Aβ production?

A

γ-secretase modulators
Alter activity to reduce Aβ production (allosteric modulators)
Don’t interfere with other γ-secretase functions
Tarenflurbil, Semagacestat ineffective or accelerate decline
Β-secretase (BACE) inhibitors
Merck Verubecestat phase 2 or 3 trial halted - no benefit
Will those only work if given very early, even before symptoms appear?
Is clearance of Aβ more important than production?

69
Q

What treatment options can be used to specifically target Aβ and plaque clearance?

A

β-sheet blockers
3-amino-1-propanesulphonic acid (3APS, Tramiprosate, Alzhemed)
Maintains Aβ in random coil in vitro
Reduces plaques and soluble Aβ40/42 in transgenic mice
No better than placebo in humans

Monoclonal antibodies
Bapineuzumab binds Aβ and promotes clearance, amyloid reduced 25%, lowers tau = failed in clinical trials
Solanezumab binds soluble Aβ = disappointing clinical trials, some success in moderate AD

70
Q

Is the amyloid hypothesis correct?

A

Disappointing results of clinical trials of drugs based on amyloid hypothesis - so far
May be due to time of administration - too late
Amyloid-β may be a “trigger” and only low amounts needed when asymptomatic
Nobody has a better alternative!

71
Q

What are some of the recent discoveries in Alzheimer’s research?

A

4-(2-hydroxyethyl)-1-piperazine propane sulphonic acid (EPPS) disaggregates plaques and improves cognition, reduces inflammation in transgenic mice.
Eat more curries! J147 (derivative of curcumin - turmeric) beneficial in AD mouse models but also in ageing mice.
Possible prion-like transmission of AD.

BoD - Neuro (4 decks)

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