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Thesis Prep > MxD > Flashcards

MxD Flashcards

1
Q

In our MxD paper, were metabolic impairments exacerbated by dementia in males only, females only, or both?

A

only in females

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2
Q

Describe the amyloid pathology findings in the MxD paper

A

females had more amyloid plaques, had greater amounts of insoluble amyloid (measured via ELISA), and greater numbers of amyloid+ cells in the cortex

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3
Q

Did we find any differences in Tau in the MxD project?

A

There were no group differences

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4
Q

Which Tau phosphorylation sites did we look at?

A

total tau
s199
PHF1

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5
Q

Describe our astrogliosis findings in the MxD project

A

We measured astrogliosis by the %area covered by GFAP+ signal. We found that there was greater hippocampal astrogliosis due to dementia in females only.

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6
Q

What was the effect of dementia on microgliosis in males?

A

dementia decreased microgliosis in the hippocampus of males only

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7
Q

What did hippocampal Iba1 expression correlate with only in females?

A

glucose intolerance

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8
Q

Did we find an effect of diet on amyloid pathology?
Have others found an effect of diet on amyloid pathology?

A

We did not see an effect of diet on amyloid pathology.
Others have found that a high fat diet increases amyloid beta pathology and in some cases specifically in females.

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9
Q

What pathological differences may underlie the sex differences in cognitive function that we observed?

A

While further sex differences in dementia pathology may develop with age, increased Aβ and astrogliosis in females support the heightened sensitivity of females to AD/MxD and may underlie the wider array of cognitive deficits in females.

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10
Q

Can a high fat diet lead to cerebrovascular remodeling?

A

Pires et al. have shown that HF diet causes cerebral vessel remodeling [63].

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11
Q

What is the effect of estrogen on amyloid pathology?

A

vii. Rodent studies have also shown protective effects of estrogen against A

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12
Q

Why might the females fare worse in the MxD project given the protective effects of estrogen?

A

we have found that AD/MxD female mice are more strongly impacted by HF diet.

The 3xTg-AD genotype may diminish the capacity of the brain to produce estrogen, given that women with AD have lower levels of brain aromatase (the enzyme that produces estrogen) [65, 67] and women with AD have lower brain estrogen levels [67].

There is evidence that estrogen’s effect may turn from protective to damaging when acting in the presence of inflammation or a disease state. For example, estrogen can increase inflammation if administered in older mice after a long period of estrogen withdrawal [68

Additionally, studies examining the impact of hormone replacement therapy on dementia risk have flagged diabetic women as a population in which HRT increases dementia risk [69]. Diabetes has been shown to diminish and sometimes reverse the protective effect of estrogen in rodent models of ischemia [70, 71].

increased hypothalamic expression of GFAP and IL-1β, as well as GFAP labeling in several hypothalamic nuclei that regulate energy balance in the HF-fed 3xTg-AD females

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13
Q

Describe the estrogen levels in the brains of women with AD

A

and women with AD have lower brain estrogen levels

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14
Q

What is the effect of HRT in diabetic women?

A

increases dementia risk

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15
Q

Is estrogen protective in rodent models of diabetic ischemia?

A

not in females

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16
Q

Were there any differences in plasma markers of diabetes?

A

3xTg-AD females did not display increased plasma levels of other diabetes markers (e.g., insulin, GIP, GLP-1, PAI-1, resistin) or peripheral inflammation

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17
Q

Why might the females be more affected by the HF diet?

A

females (WT+AD) had:
increased food intake
reduced activity
increased hypothalamic expression and labeling of GFAP

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18
Q

Summarized our HF neurogenesis findings

A

Adult hippc neurogenesis is suppressed by a high fat diet

CON females had more proliferating cells (Ki67+) and neuroblasts/immature neurons (DCX+) compared with CON males; however, HF diet reduced these cells in females to the levels of males.

Diet did not affect neurogenesis in males.

Further, the numbers of proliferating cells and immature neurons were inversely correlated with both weight gain and glucose intolerance in females only.
These effects were robust in the dorsal hippocampus, which supports cognitive processes.

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19
Q

What were the effects of HF diet on open field results in the MxD project?

A
  1. High fat mixed dementia males spent more time in the center of the box
  2. High fat females traveled less (no effect in males)
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20
Q

What were the effects of dementia on open field results in the mixed dementia project?

A
  1. High fat mixed dementia males spent more time in the center of the box
  2. Ad females moved more than males when on a lf diet
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21
Q

What were the sex differences in the open field results of the MxD project

A

In males only, HF MxD increased center time (disorientation)
in females only, diet decreased general activity

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22
Q

Which groups had intact episodic-like memory in the NOR test in the MxD project

A

WT LF F

WT LF M
WT HF M
AD LF M
AD HF M

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23
Q

What are the pathological markers of AD?

A

cortical atrophy
ventricular enlargement
neuronal loss
accumulation of amyloid deposits
presence of neurofibrillary tangels
glial cell activation
oxidative stress
decreased synaptic density

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24
Q

What is amyloid beta derived from?

A

APP

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25
Q

What is prediabetes?

A

where blood glucose levels are higher than normal but not yet high enough to be diagnosed as diabetes
elevated blood glucose levels and impaired glucose tolerance without insulin resistance- is a dementia risk factor

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26
Q

What is T2DM associated with in humans?

A

Brain atrophy
increased white matter hyperintensity volume (a sign of white matter damage)
Vascular abnormalities
Heightened neurodegeneration in AD
Increased risk of stroke particularly in women

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27
Q

What are some of the potential mechanisms through which T2DM acts

A

Impaired vascular function
Increased vascular oxidative stress
Changes to coagulation
Cerebral insulin resistance

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28
Q

How old were the mice when the diet started?

A

3 months (and 1 week after their surgery)

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29
Q

How old were the mice at tissue collection?

A

7 months

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30
Q

What were our CA1 microgliosis results?

A

no group differences in the females
a main effect of dementia in males (lower CA1 Iba1% area covered)

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31
Q

Describe our hippocampal delta IBA1 results

A

no group differences in females
a main effect of diet to reduce Iba1 expression in males

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32
Q

What were our CD68 hippocampal gene expression results?

A

no group differences in males or females

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33
Q

Describe our hippocampal GFAP expression results

A

there was a main effect of dementia to increase GFAP in females
no group differences in males

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34
Q

What is the significance of the CA1 region of the hippocampus?

A

involved in the consolidation , retrieval, and formation of memories

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35
Q

How did HF diet affect spatial learning in AD?

A

AD males, regardless of diet, did not show impairment in spatial learning

AD females showed an impairment in spatial learning only when fed a HF diet.

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36
Q

How did a HF diet affect spatial memory?

A

In females, WT+HF diet led to impairments as well as AD+ LF or HF led to impairments

In males, HF+AD led to impairments

37
Q

Have other researchers found that a HF diet leads to cognitive impairments in 3xTg mice?

A

yes

38
Q

What have others found regarding sex differences in the effect of a HF diet on cognitive impairments in 3xTg mice?

A

Others have found that cognitive impairments are exacerbated by a HF diet in 3xTg mice to a greater degree in females.

Some have found that males fare worse regarding working memory and fear conditioning

39
Q

Why are women more likely to develop AD?

A

higher risk of complications due to T2DM in women
higher rate of depression in women (depression is an AD risk factor)
sleep apnea increases after menopause, sleep disruption may impair Abeta clearance
lack of access to education
APOE4 genotype has a greater association with AD in women than in men
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400070/

40
Q

What have others found regarding astrogliosis in the 3xTgAD mouse?

A

others have found increased astrogliosis in the 3xtg mouse

41
Q

What have others found regarding Iba1?

A

Others have found that there are more Iba1+ cells in females (at 18 months old)

42
Q

What is the effect of hyperglycemia on Abeta?

A

hyperglycemia increases amyloid beta levels in the APP/PS1 mouse hippc https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497756/#!po=25.0000

43
Q

How do amyloid beta plaques contribute to neurodegeneration and cognitive impairment?

A
44
Q

What were our findings regarding the cognitive effects of MxD

A

MxD females were impaired in all four cognitive tests,
while MxD males had preserved spatial learning and ability to perform activities of daily living.

45
Q

Have other people found sex differences related to Iba1+ cells in 3xtg mice?

A

yes, at 12 months old in the sibiculum

46
Q

Did we find sex differences in the extent of microgliosis?

A

no

47
Q

Why might GTT be associated with CA1 microgliosis in females only?

A
48
Q

How does impaired GTT impact microglia?

A
49
Q

How does impaired gtt impact astrocytes?

A
50
Q

What were the recent findings regarding sex differences in tau pathology in the 3xtg mouse from the LaFerla Lab?

A

They found sex differences in hippocampal tau levels

51
Q

Was greater metabolic impairment associated with more severe hypoperfusion in females or males?

A

in females only

52
Q

Can HF diet lead to vessel remodeling?

A

yes

53
Q

How does HF diet impact adult hippocampal neurogenesis?

A

We found that it impairs it in females but not males

54
Q

What are some of the ways that HF diet could affect AD pathology?

A

increasing neuronal cell death
oxidative stress
brain atrophy

55
Q

Did we find any differences regarding uterine weight in the MxD project as a proxy for estrogen levels?

A

We found that a HF diet decreased the normalized uterine weight of AD and MxD females (not shown in the paper)

56
Q

What is the effect of gonadectomy in male 3xTg mice?

A

In male
3xTg-AD mice, gonadectomy (which reduces testosterone) increases Aβ and tau pathology but is rescued by
treatment with testosterone

57
Q

Describe the study by Xu et al (2004) where they chronically administered E2 to OVX diabetic rats and studied the effects of transient focal ischemia

A

E2 treatment increased leukocyte adhesion to vessels and extravasation in pial venules

58
Q

How does diabetic hyperglycemia impact ischemia?

A

increases ischemic brain damage

59
Q

How does amyloid affect insulin signaling?

A

Soluble amyloid oligomers have been shown to disrupt insulin signaling by causing a loss of
insulin receptors (Zhao et al., 2008).

In rodents, elevated brain amyloid beta1-42 (Aβ) levels
were associated with low circulating IGF-1, whereas increasing serum IGF-1 reduced Aβ
burden (Carro et al., 2002).

60
Q

How does OVX affect insulin receptor expression?

A

In female rats, IGF-1 gene expression was consistently decreased following both ovariectomy and reproductive senescence (Mao et al., 2012; Zhao et al., 2012). This was paralleled by increased expression of genes involved in Aβgeneration.

61
Q

What effect does estrogen have on glucose transport and glycolysis?

A

increases it

62
Q

What does estrogen (acting through the mitochondria) do the ATP production in healthy hippocampal neurons?

A

increases ATP production

63
Q

What does OVX do to mitochondrial bioenergetics?

A

ovx leads to a decline in mitochondrial bioenergetics

64
Q

What are some of the metabolic functions of the hypothalamus?

A

regulate energy balance
match food consumption with energy expenditure
receives peripheral metabolic signals

65
Q

What is insulin?

A

a hormone produced by the pancreas
it regulates the amount of glucose in the blood

66
Q

What is leptin?

A

a hormone that acts as an apatite suppressant

67
Q

ghrelin

A

a hunger hormone

68
Q

What is the orexigenic neuron type present in the arcuate nucleus?

A

NPY/AgRP expressing neurons

69
Q

What is the anorexigenic neuron type present in the arcuate nucleus?

A

POMC/cocaine and amphetamine-regulated transcript expressing cells

70
Q

What is the major site for hunger in the hypothalamus?

A

LHA

71
Q

What is the satiety center of the hypothalamus?

A

VMH

72
Q

have amyloid and tau pathology been found in the hypothalamus of AD patients?

A

yes

73
Q

What hypothalamic changes have been seen in AD and MCI patients?

A

volume loss
hypoperfusion
decreased glucose metabolism
accumulation of AD pathology (AD)
structural and functional abnormalities (AD)

74
Q

Do brains of AD patients have defective insulin signaling?

A

yes

75
Q

What is the genetic background of the 3xTg-AD mice?

A

C57BL/6;129X1;129S1/Sv

76
Q

What are the 3 genetic mutations in the 3xTg mice?

A

APPSwe
tauP301L
Psen1

77
Q

Describe the findings regarding heart mass in the physiology paper

A

no differences in males
an effect of dementia in HF fed females
and effect of diet within 3xtgAD females

78
Q

HF diet increased plasma insulin in which group in the physiology paper?

A

AD males

79
Q

Were there any group differences in plasma insulin in females in the physiology paper?

A

no differences

80
Q

What was the effect of HF diet on plasma leptin levels in males?

A

increased plasma leptin

81
Q

Did dementia increase plasma leptin in males or females on a HF diet in the physiology paper?

A

AD females on a HF diet had increased plasma leptin compared to WT females on a HF diet

82
Q

Were there any group differences in plasma Ghrelin levels?

A

No, but there were trends for lower plasma ghrelin levels in HF fed males

83
Q

What is glucagon?

A

stimulates the liver to break down glycogen and release glucose into the blood stream

84
Q

What is GLP-1?

A

enhances insulin secretion

85
Q

What is PAI-1?

A

tPA inhibitor

86
Q

What were the group differences in GLP-1 in the physiology paper?

A

AD increased plasma GLP-1 levels in HF males only

87
Q

What were the group differences in plasma PAI-1 levels in the

A

HF diet increased plasma PAI-1 levels in AD males only.

88
Q

Were there any group differences in the expression of AgRP, POMC, LepR, MCR4, or FINDC5 in the the hypothalamus?

A

no

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