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Animal models > Lecture Kiliaan > Flashcards

Lecture Kiliaan Flashcards

1
Q

mouse models for vascular factors in alzheimer’s disease

A
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2
Q

Are there treatments for AD?

A

There is no effective treatment yet

–> The focus lies on the early, asymptomatic phase, as treatment later on in the disease is not effective

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3
Q

What are the developmental stages of AD?

A
  • Latent phase in which you have no cognitive decline yet and no neuropathology (amyloid), but a cerebrovascular imparement is alreadi visible
  • Prodromal phase (ca. 5 years)
  • disease (ca. 10 years)
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4
Q

What are the risk factors for cognitive decline and Alzheimer’s disease

A
  • Age
  • midlife hypertension
  • Atherosclerosis
  • Midlife obesity
  • Stroke
  • Hypercholesterolemia
  • APOE4 allel
  • Diabetes type II
  • Atrial fibrillation
  • Homocysteine
  • Low education

Lifestyle:

  • Smoking
  • Diet
  • Physical inactivity
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5
Q

What is the nutritional status of Alzheimer patients?

A

Already in a very early stage of AD:

  • Less vitamin A, B12, C, D and E
  • Less omega 3 fatty acids EPA DHA
  • lowered selenium uridine
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6
Q

What is mediterranean-style diet associated with?

A

INVERSLY proportional to:

  • Development of frailty in community dwelling older adults
  • Incidence of hip fracture in prospective European study
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7
Q

What is a mediterranean-style diet?

A

HIGH intake of fruits, vegetables, legumes, UNSATURATED fatty acids from olive oil and Fish (DHA/EPA), whole grains, nuts, moderate wine

LOW intake of saturated fat, refined grains and red meat

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8
Q

Study in Spain: Mediterranean diet with extra-virgin olive oil or nuts to reduce incidence of major cardiovascular events in persons at high cardiovascular risk. What did it show?

A

People with Mediterranean diet people were less likely to die from cardiovascular diseases

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9
Q

New york city, study:

A

77 years of age
followed Mediterranean diet for 10 years.

Risk of developing MCI is lower in people adhering to mediterranean diet

Multi-ethnic community study in northern Manhattan New York 1393 cognitively normal participants (77 yrs), 275 developed MCI during follow-up of 4.5 yrs.

MCI : mild cognitive impairment

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10
Q

Nijmegen study research question and approach

A

Multi-factorial approach:

How does diet affect brain structure and function?

–> brain circulation (CBF) –> brain structure (white and grey matter) –> cognition

Alzheimer mice

induced Hypertension Obesity
induced stroke in mice

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11
Q

Multi-factorial way research

A

behavior
cognition
motor skills
muscle strength
animals are kept in digital ventilated cages (movement is measured in these cages)

MRI, PET scanning 11.7T:

  • cerebral bloodflow
  • neuroinflammation
  • structural + functional connectivity

Postmortem analyses:

  • biochemistry + immunohistochemistry lightssheet microscopy polarised light imaging
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12
Q

What were the investigated diets?

A

Fortasyn diet:

3.15% replaced by fish oil
DHA EPA
UMP
Choline
Phospholipids
B-vitamins
Antioxidants

Control diet:
5% fat
soy oil
coconut oil
corn oil

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13
Q

Dietary treatment in stroke

A

before:

  • acclimatization (- 39)
  • open field (-21)
  • rotard
  • grip test (-14)
  • polar test
    (-7)
  • Morris water maze
    normal Mice (2-3 months old)
    medial cerebral artery was occluded - transient ischemic stroke 30 min MCA occlusion

then:
stroke is performed
tMCAo Diet switch

Repeat:

  • Open field
  • MRI
  • rotarod
  • grip test
  • pole test
  • Ppi
  • rotarod
  • Open field ORT
  • Grip test
  • pole test
  • MRI
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14
Q

Summary of measurements/experimental design for mice dietary treatment in stroke

A
  • cognition + motor skill test
  • Neuroimaging (PET, ASL, DTI, rsfMRI)
  • Immunohistochemistry/ biochemistry
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15
Q

Cerebral bloodflow MRI Fortasyn vs control mice

A

day 7 and day 35 (even after one month there is very low blood flow in control diet), in mediterranean diet the cerebral bloodflow improved significantly after 7-35 days.

Diet restored CBF in right hippocampus at day 35 with mediterranean diet

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16
Q

Resting state fMRI functional connectivity

A

Control diet - less red squares, i.e. not so much connectivity)
Fortasyn diet - more red squares (more connectivity)

The mediterranean diet led to significantly more connectivity, especially between left and right motor cortex and more connectivity overall

(just one month of good diet!)

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17
Q

What are the results of the pole test?

A

Pole test: motor coordination

impact of diet on motor sklls after stroke

measure: rotation time –> fortasyn diet was significantly faster, i.e. mice on diet turn faster - improved motor coordination

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18
Q

uPET imaging of microglial activation

A

[18F]DPA-714 ligand for the 18 kDa translocatoprotein (TSPO), expressed by microglial cells & macrophages upon neuroinflammatory stimuli

-> VISUALIZE inflammation

control diet you see a lot of inflammation through activated microglia

in mediterranean diet you see less activated microglia, i.e. less inflammation

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19
Q

How can exercise impact be measured?

A

Impact of 1 week voluntary exercise on stroke recovery in male mice.

Design:

  • Occlusion of tMCA (30 min), leading to stroke
  • tMCAO (transient middle cerebral artery occlusion) ß most common stroke in humans
  • C57BL/6J mice

Animals put in cagen with or without running wheel and activity is monitored

After a week, animals are put in scanner (Neuroimaging (UHF 11.7 T) and immunohistochemistry

Beeficial effects on : cognition, neurogenesis, inflammation, infarct volumes

Just after one week of exercise

velocity, distance and time in running wheel is measured

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20
Q

Digital ventilated cages

A

24-7 monitoring of frequency, speed duration turning

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21
Q

WHat and when to measure activity in mice for impact of 1-week voluntary exercise on stroke?

A

ACTIVITY: They usually are active during the night, so focus on night.

LATERALITY: going to left or right

without RW: preference to go to the left

with RW: no preference

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22
Q

RW vs no RW CBF levels?

A

CBF increased in animals who had access to RW

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23
Q

1-week of RW resting state fMRI

A

Functional connectivity in significantly improved already after one week. Especially between right sensory cortex and left auditory cortex (p<0.02)

24
Q

What is the cycle leading from hypertension until a problem and repair?

A
  • Hypertension, artherosclerosis stroke influenced by lifestyle exercise medi/multinutrient diet
  • impairment vasculature (occluded vessels/plaques)
  • lower cerebral bloodflow + vascular plasticiy is lowered
  • impaired energy metabolism mitochondria
  • loss of white matter, less neurogenesis, less synapses

High fat diet then leads to neuronal dysfunction and cognitive impairment (Alzheimer’s disease)

  • but with healthy lifestyle choises this can be reversed and a repair of the brain structure and function repair can take place.
25
Q

High-fat diet (45% fat) on neurovascular function

A

functional hyperemia in rat brain compromised by high-fat diet (HFD)

4 weeks old rats 8 weeks HFD 45% fat or CD (control diet) 10% fat isocaloric

Stimulation of whisker (thick hair growing on face of mouse/cat etc.)

CBF % is measured and already after 8 weeks of high fat diet the % CBF is half of the CBF % increase in the control diet

26
Q

Other study, high-fat high sugar diet and cognition

A

2 diets:

LFCC - low-fat, complex carbohydrate
HFS - saturated fat and sugar

Animals need much more time to find the platform

Spatial learning in rats on HFS diet significantly decreased after only 1/2 months of high fat diet

27
Q

Impact of obesity and diet on the brain

A

LDLr ko mouse (cannot get rid of colesterol)

  • got high fat diet HFD for 4 months.
  • HFD + 5% Butyrate 2 months
28
Q

What is butyrate?

A

Natural product of bacterial fermentation in the colon of undigested fibers (plant polysaccharides and resistant starch)

29
Q

How does food influence gut bacteria, what is it good for?

A

Food/ ingested nutrients –> gut microbiota –> short-chain fatty acids

short-chain fatty acids –> food for epithelial cells, good for epithelium

short-chain fatty acids –> stimulated Enteroendocrine L cells in epithelial wall –> needed to create GLP-1 : hormones that go to hypothalamus and leads to lower hunger feeling

Ozempic GLP-1 : used for diabetes/obesity

30
Q

Butyrate fiber fermentation

A

Actions of butyrate released by colonic microbial fermentation of fiber on host metabolism, inflammation and carcinogenesis

31
Q

What is Butyrate good for

A
  • Food for colonocytes
  • Histone deacetylase inhibitor ( epigenetic regulation via acetylcholine-A, down reg of regulatory genes for inflammation, cell proliferation, apoptosis, and differentiation, suppress neoplastic transformation
  • Immunomodulatory
    GPCR binding, treg activation, +FOXP3 IL-10 expression, anti-inflammatory, apoptopic, cell cycle arrest, antiproliferative anti-neoplastic
  • mucosal defense
    mucus production, thight jcts integrity
    defensins, glucoronidase
  • counter-carcinogen oncogene suppression
32
Q

What does butyrate do in mice?

A

Butyrate restores HFD induced increased body weight.

Body weight is increased in high-fat diet, but when butyrate is added, the weight of the animal goes back and goes towards Chow diet

33
Q

How does butyrate influence CBF

A

Butyrate restores HFD decreased CBF in mid-adulthood.

In hippocampus CBF is restored when HFD is complemented with butyrate

34
Q

How does butyrate influence connectivity?

A

Butyrate restores HFD induced connectivity decrease in mid-adulthoof

HFD reduced FC within the somatosensory cortex and hippocampus and butyrate restores connectivity

35
Q

How does butyrate affect spatial learning and memory impairment in mid-adult obesogenic mice

A

Butyrate restores HFD induced spatial learning & memory impairment in mid-adult obesogenic mice

Mice spent more time in the area with platform

36
Q

How does butyrate affect adipocytes size in HFD fed mice?

A

Butyrate restores adipocyte size in HFD fed mice

37
Q

Adipokines in white adipose tissue

A

link between obesity, vascular factors and dementia.
fat surrounding the organs there is a lot of inflammatori factors (interleukins SAA MCP-1) growth factors (NGF, HGF but also those for
thrombosis/hypertension/atherosclerosis

38
Q

Hypertension

A

long term medical condition with elevated arterial blood pressure

39
Q

Leptin

A

increased in HFD: enhance arterial thrombosis angiogenesis, impair arterial distensibility and satiety hormone

39
Q

Hypotension

A

low blood pressure. Cardiovascular condition characterized by abnormally reduced blood pressure

40
Q

SAA

A

pro-inflammatory cytokine, macrophage infiltration adipose tissue. systemic SAA promotes artherosclerosis

41
Q

HFD affects plasma adipokine concentrations which is inhibited by butyrate

A
42
Q

How does butyrate and HFD influence microbiota composition in mid adulthood

A

There is a correlationn between fecal microbiota genus and neuroinflammation. The abundance of Dorea is higher in HFD (correlation with neuroinflammation) compared to HFDB while Bacteroidales is higher in HFDB (anti-neuroinflammation, butyrate producing bacteria)

43
Q

Summary

A
  1. Obesity and HFD may affect the brain via vascular system and/or via WAT (white adipose tissue)
  2. butyrate supplementation or fibre rich diets may serve as potential preventative for obesity and obesity-related disease, and in the long-run as preventative for dementia
44
Q

Alzheimer’s disease

A
  • AD affects over 55 million people worldwide
  • age is th emajor risk factor for AD (47% of people older than 85 years affected
  • 139 million affected in 2050
45
Q

first case of AD

A

August D(eter) 1850-1906

Alois Alzheimer (1864-1915)

got access to brain and Bielschowsky stained tissue sections from auguste D

46
Q

Plaques AD

A

beta Amyloid production from Precurser proteine (APP)
APP- transmenbrane proteine amyloid is cut free from APP through beta-Secrase and gamma-Secrase. Then, beta amyloide is stored in plaques

Different mutations (genetic)
when mutation is in the middle of beta amyloid (Dutch-Q; Italian-K; Arctic-G) causes severe CAA (cerebral amyloid angiopathy

Amyloid is mostly deposited in vessel holes

47
Q

CAA - cerebral amyloid angiopathy

A

immunofluorescent staining for beta amyloid ( you can see it attached to the vessels and wholes ) vessels.

Vessel walls become weak

48
Q

1991 discovery mutations in APP on chromosome 21 (Down’s syndrome), chromosome 14 and 1 (presenilin 1,2) > early onset AD

First Mouse models for AD in 90’s

put human mutation in mouse

A

Transgenic mouse models for AD
APPswe/PS1 dE9

  • transfection of genome fragments including promotor and exon – starts with production of beta Amyloid

-

49
Q

What types of models for AD

A

95% are sAD heterogenous pathogenesis linked to >20 genes, greatest influence ApoE4, TREM2

no/little mice models (non-humane primates)

<1% are EOAD linked to APP, PSEN1 or PSEN2 mutations

transgenic rats and transgenic mice

not very good as most people have the sAD

50
Q

The onset and progression of synaptic impairment, memory loss and beta amyloid and tau pathology in Tg mouse models

A

APP (one mutation in the APP)
- problems with mechanisms in hippocampus, but short term memory and beta amyloid pathology etc, only start quite late (9 months ca)

APP/PS1
- problems already start around month 3

3 x Tg

Aged: takes very long (very expensive)

51
Q

EOAD based IPSCs – trangenic mice major examples

A

3xTg
TgSwDI
other

52
Q

Research tools: mouse models transgenic mice (e.g. ALzheimer’s disease, APP/PS1)

A

We can measure:

  • behavior
  • cognition
  • motor skills
    blood pressure

MRI
- Brain structure (DTI, rsfMRI)
- Brain perfusion (ASL)
- Metabolism (MRS)

53
Q

APP/PS1 - blood pressure

A

Systolic blood pressure AD vs WT mice:

SBP is very hightened in AD vs WT, but SBP in AD mice at 16-month decreases over time

54
Q

Bloodflow and vasoactivity 18 month WT vs APP/PS1

A

Cerebral vasoreactivity difference betwee normal and vasoconstriction is significant in WT and not or in less brain regions significant for AbetaPP/PS1, i.e. vessels are not reacting anymore

55
Q

Where and when can beta amyloid be seen?

A

5

Animal models (10 decks)

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