The Einstein lab works with groups of women, men and gender-diverse individuals to explore how their brains and behaviour react and respond when they experience sex-specific health conditions, medical treatments or social practices.
Here, we offer more detailed information about existing research knowledge on some of the topics we study.
Facts about Estrogen
Estrogens are steroid sex hormones that carry out many physiological functions.
In females, estrogen contributes to the regulation of the menstrual cycle, bone density, brain function and movement of cholesterol throughout the body. It has been shown to promote synaptic growth in hippocampal regions in female rats (Vedder et al., 2016; Gibbs, 2000).
There are several different forms of estrogen within the human body.
Endogenous estrogen is mainly seen in the chemical structure 17β-estradiol (E2), but can also include estrone (E1) and estriol (E3). Each estrogen differs in their amount of hydroxyl (-OH) groups in order to be correctly recognized by estrogen receptor ERα or ERβ.
Estradiol plays an important role in protecting cognition.
E2 (along with certain types of Apolipoprotein E, which helps transport fat within the brain) protects against the buildup of β-amyloid proteins. These proteins form plaques that gradually build up in the synaptic cleft of neurons and prevent signaling between cells, leading to cortical tissue loss that may lead to cognitive decline.
Estrogen is secreted throughout the body.
In premenopausal women, E1 & E2 are mainly secreted by the ovaries throughout the menstrual cycle, but also may be secreted from adipose (fatty) tissues and the adrenal glands. During pregnancy, the placenta produces only E3. In postmenopausal women, estrogen synthesis is achieved through aromatase.
Estrogen is suddenly reduced by surgical menopause.
For many female carriers of the BRCA 1/2 gene (shown to be a genetic marker of greater risk for developing breast cancer), a decision may be made with their physician to undergo a prophylactic (preventative) oophorectomy (ovary removal) to greatly reduce their chances of getting breast cancer. Through an oophorectomy, a woman’s ovaries are removed and are no longer able to produce estrogen. The woman’s body immediately enters a menopausal state where circulating estrogen levels are reduced and are mainly synthesized through adipose tissues.
Facts about Alzheimer’s Disease
Alzheimer’s disease (AD) is an irreversible brain disease.
AD affects cognition and frontal brain regions and is characterized by the development of amyloid plaques and neurofibrillary tangles.
There are two distinct types of Alzheimer’s disease.
Each type has a genetic component: Early-onset Alzheimer’s (occurring in those aged 30 to 60 years old) is linked to mutations on chromosomes 1, 14 and 21. Late-onset Alzheimer’s (occurring in those after 60 years old) is linked to mutations on chromosome 19.
Most cases of Alzheimer’s Disease are late-onset.
Late-onset AD has the genetic risk factor of the ε4 gene variant of the apopoliprotein E (APOE) gene. Inheritance of ε4 has been identified as one of the factors associated with the development of Alzheimer’s disease and other forms of dementia ((Limon-Sztencel et al., 2016; Higgins et al., 1997). However, this is in no way causational and there are plenty of people with APOe4 gene who do not develop Alzheimer’s disease or dementia.
Plaques and tangles are suspects in how AD forms.
Plaques are abnormal clusters of beta-amyloid (Aβ) proteins that build up in the synaptic cleft between nerve cells to prevent signaling between these cells. This leads to cell death and cortex tissue loss in the brain that may lead to AD. Dead and dying nerve cells contain tangles, which are made up of twisted strands of tau protein that destroy the transport system within the brain, causing nutrients to cease movement through the cell. The cell then dies or loses function due to lack of nutrients.
Plaques and tangles spread throughout the brain in a predictable pattern, but the rate of Alzheimer’s progression varies greatly between people.
Earliest Alzheimer’s changes in the brain may begin many years before diagnosis, and mainly affects cortical regions involved in learning and memory, and planning. Later stages in AD affect regions involved in speech, understanding, and awareness.
The connection between estrogen, genes and Alzheimer’s
APOe4 is a genetic variant of the APOE gene.
APOe4 is found on chromosome 19 and codes for Apolipoprotein E, which is responsible for transport of fat in the brain (Johnson et al., 2014; Nathan et al, 2004). Humans have three genetic variants of the APOE gene (ε2, ε3 and ε4).
Estrogen and specific APOE alleles work together to protect against cell death caused by oxidative stress.
E2 and APOε2 work together to protect against cell death from Aβ by the 4-hydroxynonenal (HNE) metabolite in response to oxidative stress as a result of beta-amyloid plaque buildup between nerve cells.
Oophorectomy causes the body to enter a post-menopausal state.
After an oophorectomy, the body loses much of its circulating E2 (specifically 17-β-estradiol) that would normally originate from the ovaries. The presence of E2 has been shown in animal studies to promote synaptic growth in hippocampal brain regions (that are involved in memory) and protect against β-amyloid damage (Tschiffely et al., 2016; McEwen et al., 1999; Vedder et al., 2014).
Interventions post surgery can help estrogen deprivation.
Hormone Replacement Therapy (HRT) is currently used post oophorectormy to protect against E2 deprivation (Nappi et al., 2016; Shumaker et al., 2003).