BRAIN SEX DIAMORPHISMS AND DISEASE Flashcards
What diseases do males generally have more of?
ADHD, autism, dyslexia, taurettes, parkinson’s, substance abuse, schizophrenia (early onset and more severe) and stroke until menopause
What do females generally have more of?
depression, anxiety disorders, eating disorders, senile dementia – alzheimers type, and MS
What does gender epidemiological data suggest?
THESE ALL SUGGEST A ROLE FOR OESTROGENS IN THE PATHOPHYSIOLOGY
What has been one of the key studies in looking at the effects of oestrogen? What did it find
Main clinical focus: ovarian steroids in menopause and hormone replacement therapy – The Women’s Health Initiative (WHI) study. -2002- prospective, double blind crossover clinical trial intended to run for 5 years to test whether HRT was beneficial for CVS system. However, stopped after 2 years because incidence of stroke increased
-However, the group of women they chose to do this were in their 60s- had been without E2 for 10 yrs. If without E2 for long time, system adapts to be without it so when you add it back, it becomes harmful
What has the main pre-clinical focus been? Problems
Main pre-clinical experimental focus has been to investigate estrogen therapy in ovariectomised females (mainly rodents, occasionally monkeys)
-Ovariecromise, so take away oestrogen. Then give E2 back, to see if protective. But when people give back E2 in experimental situations, they give a continuous level, rather than a cyclical manner.
Few studies have considered the role of androgens or the effects of hormone treatments in male
What role does oestrogen generally have?
Pleiotropic: many targets in the brain. Development: potent neurotropic factor (influencing brain development and organization). – Migration – Neurite outgrowth – Synaptogenesis – Growth factor production – Apoptosis In the adult brain they are thought to play a role in memory and cognition as well as postural stabililty, movement and fine motor skills and Brain plasticity, e.g. neurogenesis, dendritic spine density
What are oestrogen indirect and direct actions?
Direct: Brain
Indirect: cholesterol and alters immune function that impacts brain.
Brain - promote survival by acting on cell death cascades
Promote synaptic plasticity - neurite sprouting and regeneration and modulates neuronal function and synaptic transmission
What is generally the difference between ERs?
ERα- mRNA widely distributed in many brain regions in males and females
ERβ- mRNA more restricted distribution
ERα and Erβ may co-localise; Proteins can form homo and hetero-dimers
Which area is ER alpha mainly found in? Evidence
Hypothalamus
ER mRNA expression in adjacent brain sections (coronal) of 26 yr old male - looking at radioactive ligands binding to receptor. Particularly PVN, ARC, VMH
Amygdala
Regulation of fear, emotional & stress responses, social behaviour, cognition and has Major connections with areas strongly associated with memory
Key structure implicated in affective disorders (depression, anxiety)
Therefore this provides anatomical evidence that these regions could be affected by hormones
Which area is ER beta mainly found in
Hippocampus
Subiculum - ER β dominated where information leaves the hippocampus to influence amygdala, cortical and subcortical structures
Cortex- ERb dominant regions
Are oestrogen actions in the brain ER mediated?
- rapid actions in culture (Many studies in cultured cells-but brain neurons only grow in culture at a very young age, how relevant to actual adult cells?)
- ERKO studies - conflicting reports
- some suggestions ER-dependent effects occur at physiological concentrations whilst ER-independent effects occur at pharmacological doses (is the relevance of using 10/100 thousand fold concs of estrogen- higher levels may not be working via the estrogen receptor)
What are experimental ways to damage the brain cells? Eg for different disease? And what tissue is used
Generally use primary neuronal cultures e.g. neuroblastoma and pheochromocytoma.
Post stroke – glutamate released. Glutamate is an excitotoxin, but too much is toxic.
For parkinsons disease, selectively use dopaminergic killing such as 6-ohda and mptp
Mitochondrial toxins
Hydrogen peroxide
Serum- needed to grow, has nutrients and growth factors to allow healing to occur. Serum deprivation causes cell to die.
Add amyloid B peptide to cell lines and cultures- Alzheimers.
In the absence of any disease model, one experiment to show the effects of oestrogen?
Gave peroxide to challenge cells and then gave oestrogen treatment to see if cells survived. Was a signficant increase in cell survival numbers.
Protective effects not blocked by ICI182 780 (ER antagonist), which has some protective effects of its own.
What are the two hallmark features of Alzheimer’s disease? What correlates with memory and cognitive decline>
– Diffuse neuritic plaques predominantly composed of Amyloid β peptide (underlies synaptic dysfunction)
– Neurofibrillary tangles composed of filamentous aggregates of hyperphosphorylated tau protein
• Loss of neuronal synaptic density correlates with memory and cognitive decline better than the extracellular plaque or tangle formation and precedes neuronal loss.
Which animal model is used to model Alzheimer’s?
The mouse triple transgenic model:
• PS1(Presenilin-1) Mutations in gene causally linked to many cases of early onset AD. Up-regulation linked to increased vulnerability to excitotoxic injury
• APP (amyloid precursor protein)
• Tau protein
The increase in Aβ accumulation and tau hyperphosphorylation in the hippocampus, subiculum and frontal cortex. decline in working memory performance with aging occur to a far greater extent in 3x-tg AD mice compared with WT.
What 3 bits of evidence is there for oestrogen’s actions in Alzheimer’s disease?
1: in TTG mice, oestrogen lead to decreased BETA AMYLOID deposition in the prefrontal cortex, the subiculum and Ca1. This was measured by ovx sham (low), ovx (high) and ovx and E2 (low)
2: at 6 months of age, oestrogen lead to decreased TAU PHOSPHORYLATION. Same results as above. But there were low n numbers and large error bars.
3: E2 regulates spontaneous alternation behaviour (Y-maze, memory test) in 3xTg-AD but not WT mice
In 3xTg-AD, decreased spontaneous alternation behaviour in ovariectomised animals. Treating with E2 in 3xTg-AD transgenic animals can restore memory.
Ovx wild mice had no effect
What is the effect of progesterone on alzheimers? 2 evidence - think 2 different ways that alzheimers acts
Progesterone attenuates the effects of E2 on AB accumulation in 3xTg-AD mice
OVX (When you ovariectomise, also removing progesterone), OVX+P4, OVX +E2+P4
So OVX+P4- does not have an effect
OVX+P4+E2- also prevents E2 from having its effect on decreasing AB load
But in this study, did not give OVX+E2 on its own. Should have had this as another control
P4 reduces tau hyperphosphorylation in ovx 3xTg-AD mice
In this case, progesterone doesn’t interfere with effect of estrogen
Progesterone- beneficial in effects on tau, but not AB
Only used one dose of these hormones- limitation
What do oestrogen and progesterone results for alzheimer’s suggest?
That there could be an optimum hormonal therapy to treat alzheimers. Due to the different presence of ERa and ERb across different brain regions, oestrogen has different effects in different areas in beta-amyloid accumulation. These results support continued investigation of SERMs as an alternative to oestrogen-based HT in reducing the risk of AD in postmenopausal women.
How might oestrogen be acting in alzheimer’s disease?
Genomic signalling- Estrogen may be signalling through CRE and ERE on BCL-2 family- genes involved in anti-apoptotic pathway
Non-genomic signalling- can activate PI3K, PKC cascades- these reduce apoptosis
Affects non-amyloidogenic processing of AB precursor protein
Increased expression of Neprilysin, enzyme that breaks down AB, and IDE enzymes