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Applied Pathophysiology > Alzheimer's Disease (AD) > Flashcards

Alzheimer's Disease (AD) Flashcards

1
Q

What is Dementia?

A

a term used to describe severe changes in the brain that cause memory loss. These changes also make it difficult for people to perform basic daily activities.

In most people, dementia causes changes in behavior and personality.

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2
Q

What 3 areas of the brain does Dementia affect?

A
  • language
  • memory
  • decision-making
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3
Q

What is Dementia caused by?

A

Most cases of dementia are caused by a DISEASE and CAN’T BE REVERSED.

  • (EXCEPTION) Alcohol and drug abuse can sometimes cause dementia. In those cases, it can be possible to reverse the damage in the brain. But reversal happens in fewer than 20 percent of people with dementia.
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4
Q

What is the epidemiology of Dementia?

A
  • Someone in the world develops dementia every 3 seconds.
  • Currently >50 million but by 2030 ~75 million people will have AD.
  • Much of the increase will be in developing countries. Already 58% of people with dementia live in low and middle income countries, but by 2050 this will rise to 68%.
  • The fastest growth in the elderly population is taking place in China, India, and their south Asian and western Pacific neighbours.
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5
Q

What is the most common type of Dementia?

A

Alzheimer’s disease

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6
Q

What do early signs of AD include?

A

depression, forgetting names and recent events, and depressed mood.

However, depression is NOT PART of Alzheimer’s disease.

It’s a separate disorder that must be treated specifically.

Occasionally, depressed older adults are misdiagnosed as having Alzheimer’s disease.

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7
Q

What is AD characterized by?

A

characterized by NEURONAL DEATH.

As the disease progresses, people experience confusion and mood changes.

They also have trouble speaking and walking.

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8
Q

What age group is most likely to develop AD?

A

Older adults

(only ~5% of cases are early onset - 40s or 50s)

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9
Q

Which part of the brain is affected in AD?

A

The Limbic System

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10
Q

What is the Limbic System?

A

a complex set of structures that lies on both sides of the thalamus, just under the cerebrum (BRAIN). It includes the hypothalamus, the hippocampus, the amygdala, and several other nearby areas.

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11
Q

How is the Limbic System the part of the brain that is affected in AD?

A

It appears to be primarily responsible for our EMOTIONAL LIFE and has a lot to do with the formation of memories, and hence is important in AD.

It THEN reaches frontal cerebral cortex AFFECTING SPEECH & MOVEMENT.

Damage to parietal lobe AFFECTS LANGUAGE.

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12
Q

What are the 2 distinctive pathologies in an AD brain?

A
  • neurofibriallary tangles (abnormal intracellular aggregates)
  • neuritic plaques (miliary foci) (dystrophic neuronal processes surrounding a “special substance in the cortex”)
  • brain shrinks, gyri narrow, sulci widen, ventricles get larger
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13
Q

What does a AD brain look like?

A
  • brain cortex atrophy (shrinks)
  • gyri get narrower
  • sulci get wider
  • ventricles get larger
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14
Q

What is apart of the AD diagnosis?

A
  1. Brain cortex atrophy
  2. Amyloid plaques (Senile plaques) and NeuroFibrilary Tangles (NFT).
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15
Q

Alzheimer Senile Plaques:

A

Immunohistochemistry of affected Alzheimer’s tissues using antibodies directed against Aβ PEPTIDES demonstrates the presence of both diffuse (a) and dense core (b) senile plaques.

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16
Q

Neurofibrillary tangles:

A

contain FILAMENTOUS TAU and correlate with disease severity.

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17
Q

What are Senile Plaques (Amyloid Plaques)?

A
  • Are composed mainly of Amyloid-beta
  • Aβ is generated by sequential processing of AMYLOID PRECURSOR PROTEIN (APP). Aβ42 is more toxic: more hydrophobic (bind to each other) and more oligogenic.

(come together & form clumps; NFT’s)

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18
Q

What is APP?

A

a single-pass transmebrane protein. Might be involved on neuronal development and function. Loss of APP is fatal.

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19
Q

Non-amyloidogenic processing is by…

A

α-secretase followed by γ-secretase.

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20
Q

Amyloidogenic involves…

A

β-secretase(BCAE1)andγ- secretase.

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21
Q

Where is Aβ secreted?

A

into the interstitial fluid via a pathway that is enhanced in the setting of neuronal activity.

Aβ42 is the diseased form.

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22
Q

What happens following secretion?

A

Aβ aggregates into oligomers and fibrils that have numerous effects on cellular function including impaired synaptic activity and synapse loss, and impaired cerebral capillary blood flow.

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23
Q

Aβ directly promotes…

A

Tau pathology by stimulating tau hyperphosphorylation as well as other pathways.

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24
Q

What does Nonamyloidogenic processing of APP involve?

A

α-secretase followed by γ-secretase

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25
Q

What does Amyloidogenic processing of APP involve?

A

BACE1 (β-secretase) followed by γ- secretase is shown. Both processes generate soluble ectodomains (sAPPα and sAPPβ) and identical intracellular C-terminal fragments (AICD).

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26
Q

What are Neurofibrillary tangles?

A
  • TAU is the major microtubule associated protein (MAP) of a mature neuron.
  • MAPs interact with tubulin and promote its assembly into microtubules and stabilize the microtubule network.
  • PHOSPHORYLATION OF TAU DECREASES ITS MICROTUBULE ASSEMBLY promoting activity: Normal adult human brain tau contains 2–3 moles phosphate/mole of tau protein..
27
Q

What is Tau in an AD brain?

A

∼three to four-fold more hyperphosphorylated than the normal adult brain and in this hyperphosphorylated state it is polymerized into paired helical filaments ([PHF) admixed with straight filaments (SF) forming neurofibrillary tangles.

28
Q

What might be a promising therapeutic target for AD & related tauopathies?

A

Inhibition of abnormal hyperphosphorylation of tau

29
Q

What is Presenilin : (a subunit of γ-secretase)?

A
  • Mutations in the PSEN1 gene, encoding presenilin-1 (PS1), are the most common cause of FAMILIAL Alzheimer’s disease (FAD). (1 of the most imp. cofactor in AD’s is having mutations in the PSEN1 gene)
  • PS1 functions as the catalytic subunit of γ-secretase that cleaves amyloid precursor protein (APP).
  • Mutation of PS1 increases the amyloidogenic proceesing of APP (more production of Aβ42).
30
Q

What is Oxidative Stress?

A
  • Reactive Oxygen Species production is increased in aging.
  • There is a gradual loss of ANTIOXIDANTS including Glutathione and Thioredoxin protein.
  • Increased ROS and decreased antioxidants cause OXIDATIVE STRESS.
  • Evidence of increased oxidative stress is shown by increased protein oxidation.
  • Increased Oxidative stress can aggravate amyloid beta toxicity by activation of immune cells.
  • Oxidative stress can activate proteins kinases and inhibit dephosphorylating enzymes, causing Tauopathy.
  • Oxidative stress (can occur from not eating or sleeping well for ex) is sufficient for increased Aβ deposition.

**IN AD’s brain there is:
- INCREASE in oxidative stress b/c there’s A LOT of oxidized protein & DECREASE level of antioxidants

31
Q

What can help AD in terms of Oxidative Stress?

A

exercise, decreased calorie intake

32
Q

What are the 4 AD pathophysiologies?

A
  1. Senile Plaques (Amyloid Plaques)
  2. Neurofibrillary Tangles
  3. Presenilin
  4. Oxidative Stress
33
Q

What is the therapy for AD?

A
  • non disease-modifying therapy
  • life intervention
  • symptom relief
  • clinical trial failures

(prevent it from getting worse)

34
Q

What is Aβ antibacterial role?

A
  • Aβ in vitro has similar antimicrobial activity to LL-37 (a standard anti-bacterial compound used as a scale).
  • Mouse lacking both BACE1/2 (not producing Ab) are more susceptible to pathogens.
  • Aβ has also been shown to be protective against viral infections such as Herpes simplex virus 1 (HSV-1).
35
Q

What is Neuroinflammation?

A

is the inflammatory response (to pathogens/damage) within nervous tissue

  • can cause damage to the brain! It may be as important as NFT and Amyloid plaques in pathogenesis of AD.
36
Q

What are the inflammation mediators?

A

Cells & chemicals

37
Q

What are the Microglia’s role in neuroinflammation?

A

1) cellular surveyors for pathogens (at rest)

2) Pruning synapses, producing growth factors (BDNF) and contributing to memory
formation.

3) Innate immunity (Response to dead neurons and damaged proteins/(Aβ)

4) Contain receptors that identify
damage/pathogens (Damage /Pathogen associated molecular patterns (DAMP/PAMP)

5) Has receptors (CD36, CD14, TLR4 TREM2) to bind to Aβ42 causing their activation (inflammation).

6) Increases secretion of PRO-INFLAMMATORY CYTOKINES through INFLAMMASOME ACTIVATION.

7) Decreased receptor affinity, cause increased Aβ42 deposition.

38
Q

What are the Astroglia’s role in Neuroinflammation?

A

major supporting cells (provide nutrition in response to pathological status include:

1- Next to activated microglia, HYPERTROPHIC REACTIVE ASTROCYTES accumulate around senile plaques and are often seen in post-mortem human tissue from patients with Alzheimer’s disease, and in animal models of the disorder.

2- Reactive astrocytes are characterized by increased expression of glial fibrillary acidic protein (GFAP) and signs of FUNCTIONAL IMPAIRMENT; however, astrocytes do not seem to lose their DOMAIN ORGANIZATION, and no evidence of scar formation exists in AD .

3-Changes in astrocyte shape may affect their interactions with neurons because of their modulatory role in synapses.

39
Q

In addition to neuroinflammation, there may be other physiologically relevant cellular stressors that trigger APP and BACE1 and promote Aβ generation in astrocytes:

A
  • GLUCOCORTICOIDS: Under stress
  • TISSUE LESIONS: Hippocampus tissue stimulate APP expression in nearby astrocytes .
  • INORGANIC ARSENIC (iAs), a toxic metalloid, can contaminate drinking water and is associated with cognitive impairment. Cells process iAs to a highly toxic monomethylarsonous acid (MMA), which has been suggested to be associated with neurodegenerative disorders,.
40
Q

What are Endotoxins?

A

type of lipopolysaccharide: consist of Lipid A, attached to a core of sugars and attached to a longer chain of sugars (O-Antigen).

41
Q

Where are Endotoxins found?

A

in gram-negative bacteria cell wall.

in the gut, saliva, gums and dental plaques, skin, lungs,
respiratory tract and urinary tract.

42
Q

When are Endotoxins released?

A

after bacterium death or secrete from bacteria.

  • Depending on the type, endotoxins may be pro-or anti-inflammatory.
    (depends on the O antigen)
  • About 1g on endotoxin is found in human gut, and injection of 100ng into a
    rodent blood can cause neurodegeneration: humans are much more sensitive.
43
Q

Endotoxin Theory of Neurodegenerative Diseases:

A

Endotoxin is present in plasma of all healthy humans at very variable levels between about 1 and 50 pg /ml

  • SERUM ENDOTOXIN LEVLELS ARE ELEVATED in patients with severe autism, liver cirrhosis, diabetes, cardiovascular disease, chronic infection and ageing, amyotrophic lateral sclerosis and Alzheimer’s disease. The highest plasma endotoxin levels are found in patients with sepsis, about 500 pg/ml (up to 500pg).
  • Addition of 10pg/ml endotoxin (intravenous) in rodents is sufficient to activate monocytes and endothelial cells and increase inflammatory cytokines levels (TNFa).
44
Q

What is associated with Dementia?

A

Chronic infections such as Kidney disease is associated with dementia. Gingivitis may also increase the chance to develop dementia.

45
Q

What is the central pathway for how endotoxin leads to neurodegeneration?

A

Gut/gum endotoxin or infections –> Blood endotoxin –> Brain inflammation –> Neurodegeneration

46
Q

What is AD divided into 2 subtypes?

A
  • early-onset AD (EOAD)
  • late-onset AD (LOAD)
47
Q

EOAD accounts for…

A

approximately 1% to 6% of all cases and ranges roughly from 30 years to 60 or 65 years.

48
Q

LOAD…

A

is the most common form of AD, onset is later than 60 or 65 years.

49
Q

Both EOAD and LOAD may occur in people with a…

A

positive family history of AD.

50
Q

Early-onset disease can also occur in families with…

A

LOAD

51
Q

Most AD cases appear to be a complex disorder that is likely to involve multiple…

A

susceptibility genes and environmental factors.

52
Q

The pattern of transmission is rarely consistent with…

A

Mendelian inheritance

53
Q

What are the genetic risk factors for AD?

A

There are four genes linked to AD: Three cause familial and one SPORADIC.

  • 1-APP (Amyloid precursor protein).
    • Gene is located on chromosome 21.
  • People with trisomy 21(Down syndrome) show early onset

2- SP1 (PSEN1) or presenelin-1 is responsible for the γ-secretase cleavage of APP. Defects in PSEN1 cause the most severe forms of AD, with complete penetrance and an onset occurring as early as 30 years of age.

3-SP2 (PSEN2) or presenelin-2 located in chromosome 1, mutations in this gene are rare and affect the γ-secretase cleavage of APP.

4-ApoE: APOE is the strongest genetic risk factor for LOAD. (Sporadic).
* ApoE has FOUR isoform (E1-4).
* Having one E4 allele increases risk of AD developing by 3-4X, two copies=12 times

54
Q

What are non-modifiable risk factors for AD?

A
  • Age
  • Gender (female > male)
  • Family history
  • Race
  • Down’s Syndrome
  • ApoE-e4 allele
  • Cerebral amyloidosis-a biomarker of the AD patho process
55
Q

What are the improving health factors to decrease AD?

A
  • Exercise
  • Mediterranean Diet
  • Reduced Calorie intake (National Institute of aging)
  • Intermittent fasting (improving insulin levels, vascular dementia caused by interruption of blood supply to the brain, micro strokes).
56
Q

What are the Non-pharmacological treatments?

A

first line option to treat neuropsychiatric symptoms (e.g., agitation, apathy, delusions, disinhibition) and problem behaviors (e.g., resistance to care, caregiver shadowing, hoarding, obsessive compulsive behaviors) in AD dementia.

  • Supplemental medicine/vitamins
  • Vitamin E may be effective in delaying the cognitive decline
57
Q

What are the Pharmacological treatments?

A

The current AD medication treatment aims to reduce progression of symptoms and disability: FDA approved drugs:
* 1- Acetyl Cholinestrase inhibitors: donepezil, galantamine, and rivastigmine,
* 2-N-methyl-d-aspartate (NMDA) antagonist memantine, (inhibits NMDA receptor-mediated
hyperactivity/toxicity) in more sever cases/stages

  • These are administered to reduce progression of clinical symptoms and disability.
  • These therapies aim to minimize caregiver burden and delay the need for long-term care home.

(tries to maintain function of dying synapse)

58
Q

AD is mostly the disease of…

A

aged people. (Age is the most important risk factor)

59
Q

Many aspects of AD remains to be…

A

understood

60
Q

Accumulation of ___ and ___ are the major histopathological markers of the disease but may be the result of neuronal defence system against factors remaining to be identified.

A

Aβ and Tau

61
Q

_______ is an important player in pathology of AD, resembling a double- edged sword.

A

Inflammation

62
Q

_________ and _________ can affect the disease.

A

Healthy lifestyle and socioeconomic status

63
Q

Current drugs only ______ the symptoms.

A

alleviate

The need for more research and new drugs remain high.

Applied Pathophysiology (34 decks)

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