MxD

Question 1

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

Answer 1

only in females

Question 2

Describe the amyloid pathology findings in the MxD paper

Answer 2

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

Question 3

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

Answer 3

There were no group differences

Question 4

Which Tau phosphorylation sites did we look at?

Answer 4

total tau
s199
PHF1

Question 5

Describe our astrogliosis findings in the MxD project

Answer 5

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

Question 6

What was the effect of dementia on microgliosis in males?

Answer 6

dementia decreased microgliosis in the hippocampus of males only

Question 7

What did hippocampal Iba1 expression correlate with only in females?

Answer 7

glucose intolerance

Question 8

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

Answer 8

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.

Question 9

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

Answer 9

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.

Question 10

Can a high fat diet lead to cerebrovascular remodeling?

Answer 10

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

Question 11

What is the effect of estrogen on amyloid pathology?

Answer 11

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

Question 12

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

Answer 12

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

Question 13

Describe the estrogen levels in the brains of women with AD

Answer 13

and women with AD have lower brain estrogen levels

Question 14

What is the effect of HRT in diabetic women?

Answer 14

increases dementia risk

Question 15

Is estrogen protective in rodent models of diabetic ischemia?

Answer 15

not in females

Question 16

Were there any differences in plasma markers of diabetes?

Answer 16

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

Question 17

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

Answer 17

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

Question 18

Summarized our HF neurogenesis findings

Answer 18

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.

Question 19

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

Answer 19

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)

Question 20

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

Answer 20

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

Question 21

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

Answer 21

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

Question 22

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

Answer 22

WT LF F

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

Question 23

What are the pathological markers of AD?

Answer 23

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

Question 24

What is amyloid beta derived from?

Answer 24

APP

Question 25

What is prediabetes?

Answer 25

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

Question 26

What is T2DM associated with in humans?

Answer 26

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*

Question 27

What are some of the potential mechanisms through which T2DM acts

Answer 27

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

Question 28

How old were the mice when the diet started?

Answer 28

3 months (and 1 week after their surgery)

Question 29

How old were the mice at tissue collection?

Answer 29

7 months

Question 30

What were our CA1 microgliosis results?

Answer 30

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

Question 31

Describe our hippocampal delta IBA1 results

Answer 31

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

Question 32

What were our CD68 hippocampal gene expression results?

Answer 32

no group differences in males or females

Question 33

Describe our hippocampal GFAP expression results

Answer 33

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

Question 34

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

Answer 34

involved in the consolidation , retrieval, and formation of memories

Question 35

How did HF diet affect spatial learning in AD?

Answer 35

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.

Question 36

How did a HF diet affect spatial memory?

Answer 36

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

Question 37

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

Answer 37

yes

Question 38

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

Answer 38

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

Question 39

Why are women more likely to develop AD?

Answer 39

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/

Question 40

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

Answer 40

others have found increased astrogliosis in the 3xtg mouse

Question 41

What have others found regarding Iba1?

Answer 41

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

Question 42

What is the effect of hyperglycemia on Abeta?

Answer 42

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

Question 43

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

Question 44

What were our findings regarding the cognitive effects of MxD

Answer 44

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

Question 45

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

Answer 45

yes, at 12 months old in the sibiculum

Question 46

Did we find sex differences in the extent of microgliosis?

Answer 46

no

Question 47

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

Question 48

How does impaired GTT impact microglia?

Question 49

How does impaired gtt impact astrocytes?

Question 50

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

Answer 50

They found sex differences in hippocampal tau levels

Question 51

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

Answer 51

in females only

Question 52

Can HF diet lead to vessel remodeling?

Answer 52

yes

Question 53

How does HF diet impact adult hippocampal neurogenesis?

Answer 53

We found that it impairs it in females but not males

Question 54

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

Answer 54

increasing neuronal cell death oxidative stress brain atrophy

Question 55

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

Answer 55

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

Question 56

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

Answer 56

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

Question 57

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

Answer 57

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

Question 58

How does diabetic hyperglycemia impact ischemia?

Answer 58

increases ischemic brain damage

Question 59

How does amyloid affect insulin signaling?

Answer 59

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).

Question 60

How does OVX affect insulin receptor expression?

Answer 60

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.

Question 61

What effect does estrogen have on glucose transport and glycolysis?

Answer 61

increases it

Question 62

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

Answer 62

increases ATP production

Question 63

What does OVX do to mitochondrial bioenergetics?

Answer 63

ovx leads to a decline in mitochondrial bioenergetics

Question 64

What are some of the metabolic functions of the hypothalamus?

Answer 64

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

Question 65

What is insulin?

Answer 65

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

Question 66

What is leptin?

Answer 66

a hormone that acts as an apatite suppressant

Question 67

ghrelin

Answer 67

a hunger hormone

Question 68

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

Answer 68

NPY/AgRP expressing neurons

Question 69

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

Answer 69

POMC/cocaine and amphetamine-regulated transcript expressing cells

Question 70

What is the major site for hunger in the hypothalamus?

Answer 70

LHA

Question 71

What is the satiety center of the hypothalamus?

Answer 71

VMH

Question 72

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

Answer 72

yes

Question 73

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

Answer 73

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

Question 74

Do brains of AD patients have defective insulin signaling?

Answer 74

yes

Question 75

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

Answer 75

C57BL/6;129X1;129S1/Sv

Question 76

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

Answer 76

APPSwe tauP301L Psen1

Question 77

Describe the findings regarding heart mass in the physiology paper

Answer 77

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

Question 78

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

Answer 78

AD males

Question 79

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

Answer 79

no differences

Question 80

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

Answer 80

increased plasma leptin

Question 81

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

Answer 81

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

Question 82

Were there any group differences in plasma Ghrelin levels?

Answer 82

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

Question 83

What is glucagon?

Answer 83

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

Question 84

What is GLP-1?

Answer 84

enhances insulin secretion

Question 85

What is PAI-1?

Answer 85

tPA inhibitor

Question 86

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

Answer 86

AD increased plasma GLP-1 levels in HF males only

Question 87

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

Answer 87

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

Question 88

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

Answer 88

no