Physiological reduction of the gonadal sex hormones in old ages results in declined neurogenesis especially in the hippocampus with the resultant age dependent memory and executive functions regressions.
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Alzheimer's disease and sex hormones
1.
2.
3.
4. ◘ Cognition is a group of mental processes
by which the individual acquires and
process information to allow him to
perform his daily functions.
5.
6. ◘ The gender neurocognitive dimorphism
had noticed since antiquity which made
the old man believed in the myth:
7. ◘ This gender cognitive difference does not
appear only after puberty but it starts
since the intrauterine life.
◘ Genetic studies revealed that X-
chromosome carry genes which
expressions enhance visuospatial,
executive, and social cognitive tasks.
◘ Genes on Y-chromosome are more
responsible for behavioral sexual
differentiation.
8. ◘ During infancy and childhood, the brain
has the ability to synthesizes sex neuro-
steroids from cholesterol by the action of
aromatase enzyme resulting in different
gender cognitive performance from these
early stages of life.
9. ◘ Volumetric brain imaging showed that
females have larger frontal and medial
paralimbic cortices while males exhibit
bigger medial frontal cortex, amygdala
and hypothalamus.
◘ Neurocognitive tests revealed better
male performance in mathematics and
3D spatial tests while females are
superior in autobiographic and episodic
memories as well as verbal tasks.
10. ◘ Regarding spatial navigation, males
perform better in allocentric strategy
but females excel in egocentric
navigation.
◘ Functional MRI with virtual reality
maze, revealed different gender brain
activation in the same tests:
- Left hippocampus in males.
- Right parietal and prefrontal cortices
in female.
WomenMen
11.
12. ◘ The sex steroid hormones are potent
regulators of neuronal survival, and
functions.
◘ Physiological reduction of the gonadal
sex hormones in old ages results in
declined neurogenesis especially in the
hippocampus with the resultant age
dependent memory and executive
functions regressions.
13. ◘ Each sex steroid hormone has 2 types of
receptors; nuclear and membrane.
◘ The nuclear receptors are responsible for
the genomic action through regulation of
transcriptional gene expression.
◘ The membrane receptors are G protein-
coupled and ligand-gated ion channels
responsible for the rapid non-genomic
actions through recruitment and
activation of kinase-dependent pathways.
14. (1) Promotes neurogenesis, neuronal plasticity, and survival by stimulating nerve
growth and brain-derived neurotrophic factor.
(2) Promotes synaptic pruning and plasticity.
(3) Antiapoptotic action by regulating mitochondrial functions, stimulating anti-
apoptotic proteins and decreases free radical production.
(3) Anti-inflammatory actions by reducing the response of astrocyte to chemokines.
(4) Enhances the maturation of oligodendrocyte precursor cells and improves their
ability for CNS repair.
15. (1) Enhances hippocampal memory
consolidation, spatial navigation
memory, novel objects recognition and
object placement tasks.
(2) Increases cerebral blood flow by
enhancing endothelial derived nitric
oxide and prostacyclin pathways.
(3) Improve choline acetyltransferase, serotonergic, dopaminergic and
GABAergic activities which in turn enhances cognitive functions.
16.
17. (1) The inter-balance between sex steroids levels may change their
neurocognitive effects as in pregnancy when simultaneous increase in
progesterone and estrogens results in impaired mood and decreased
memory.
(2) Sex hormones have maximum neurobehavioral effects in the prepubertal
period with decreased neuronal sensitivity to their actions with
advancement of age.
18.
19. ◘ AD is the most common cause of late onset
dementia which is characterized by
progressive memory decline and persistent
cognitive impairment enough to interfere
with the person’s performance of the usual
daily activities.
◘ AD is not an accelerated aging but it is
characterized by distinct temporo-spatial
brain pathological changes.
20. ◘ AD disproportionately affects both
sexes with females have 2–3 times
higher incidence of AD than males of
the same age.
◘ At the same time, women have a
higher frequency of am-MCI – AD
conversion and higher speed of AD
clinical deterioration.
21. Alois Alzheimer (1864 – 1915)
Auguste Dieter (1850 – 1906)
◘ In 1838, Jean Etienne Esquirol put
menstrual disorders and sequalae of
delivery as direct causes of dementia in
his book Des Maladies Mentales.
◘ The first reported case by the German
Neuropathologist, Alois Alzheimer
was a women, Auguste Dieter, in 1901.
27. ◘ Responsible for cognitive impairment in early AD before manifest neuronal loss takes place :
(1) Serotonergic denervation in the hippocampus and neocortex.
(2) Depletion of the cholinergic neurons in the basal forebrain.
(3) Loss of > 70% of noradrenergic locus coeruleus neurons.
(4) Reduction of dopamine, dopamine metabolites, and dopamine receptors.
(5) Histaminergic tuberomammillary nucleus degeneration.
(6) Impaired melatonin secretion and action in the pineal body and suprachiasmatic
hypothalamic nucleus respectively.
29. (1) Estrogen supplements or those with late menopause are at significantly
decreased risk of AD development.
(2) Early menopause is associated with higher risk of AD in later life.
(3) Women with AD had lower estrogen levels in both blood and CSF compared
to healthy controls.
(4) Female CSF–E2 level is positively correlated with CSF–Aβ level and
hippocampal glucose metabolism in PET scan.
30. (1) Decreasing Aβ production:
- Enhancement of non-amyloidogenic α-secretase activities.
- Inhibition of amyloidogenic pathway by inhibition of β-secretase activities.
(2) Promotion of Aβ clearance:
- Stimulation of APP-containing vesicle budding by trans-Golgi network.
- Stimulation of enzymes involved in Aβ degradation including
metalloproteases–2 and –9, insulin degrading enzyme and neprylisin.
- Stimulation of microglial Aβ phagocytosis.
31. (1) Inhibition of tau phosphorylation through inhibition of protein kinases.
(2) Promotion of tau de-phosphorylation through enhancement of protein
phosphatase 2A enzyme activities.
(3) Increasing dendritic spines densities, promoting synaptogenesis, inhibiting
the neurotoxic effects of oxidized low-density lipoproteins and glutamate,
improving mitochondrial functions and enhancing the hippocampal
cholinergic neurotransmitter system.
32. (4) Estrogens also, regulate the epigenetic DNA methylation and miRNAs
biogenesis especially in the hippocampus.
(5) Estrogen increases the of antiapoptotic Bcl-xL and Bcl-w and suppressing
the expression of proapoptotic Bim which lead to prevention of neuronal
loss from Aβ toxicity.
(6) Estrogen is one of the regulators of neuronal autophagy (autophagosomes
and lysosomes) and its deficiency results in disturbed self-eating, catabolic
process.
34. ◘ The neuroprotective effect of estrogen is not the same in male sex due to
different expression of the estrogen receptors:
(1) The CSF estrogen levels in males have no
relations with Aβ accumulation in PET scan.
(2) Estrogen administration in male to female
cross sex subjects' results in significant
decreases in the hippocampal volume.
35. ◘ Women are at increased risk of AD :
(1) The baseline pre-pubertal gender
dependent neurocognitive difference.
(2) The sharp menopausal decline in
gonadal sex hormones.
(3) Spending a large proportion of life in
the postmenopausal period due to the
increased life longevity with the
resultant prolonged hypoestrogenic state.
36.
37. ◘ Unlike estrogen, studies in progesterone
neuroprotective actions are little.
◘ The neurocognitive effect of
progesterone is controversial.
◘ Some studies showed that progesterone
reduces cerebral blood flow which in
turn impairs cognitive functions.
38. ◘ Progesterone neurocognitive action is exerted either directly or indirectly
through enhancement of estrogen actions and includes:
(1) Inhibition of tau hyper-phosphorylation.
(2) Inhibition of Aβ accumulation through:
- Inhibition of amyloidogenic pathway by inhibition of β-secretase activities.
- Enhancement of non-amyloidogenic α-secretase pathway.
- Increasing Aβ clearance by enhancing insulin degrading enzyme expression
and down-regulation of β-secretase gene expression.
40. (1) Testosterone level is lower in men with AD relative to normal age matched
control both in the blood and CSF.
(2) Sex hormone binding globulin is significantly higher in AD patients.
(3) APOE-4 allele is associated with significantly lower testosterone level.
(4) The Baltimore Longitudinal Study on Aging had detected significantly
lower testosterone level 5–10 years in healthy men prior to their
development of clinically manifest AD compared to those who did not
develop AD .
(5) Short term testosterone administration improves cognitive functions in MCI
and AD patients through its non-genomic transmembrane actions.
41. (1) Enhancement of non-amyloidogenic APP pathway.
(2) Promoting Aβ clearance by stimulation of the degrading enzymes action.
(3) Postmortem studies showed that, brain levels of testosterone were inversely
correlated with cerebral soluble Aβ which precedes insoluble fibrillar Aβ
accumulation.
(4) Androgens inhibit the release of gonadotropin luteinizing hormone
secretion by the negative feedback which increases Aβ production by
enhancement of β-secretase amyloidogenic pathway.
42. ◘ Male andropause occurs very slowly
over a long period of time where free
testosterone level starts to decline in
thirties in a rate 2–3% per year.
◘ This slow andropause relative to the
rapid menopause may be one of the
explanations of decreased male
gender AD risk, delayed male
MCI/AD conversion and slower AD
cognitive deterioration.
43. ◘ Androgens especially anabolic steroids
are not always neuro-behaviorally
beneficial and their short-term use
results in aggressive and manic behaviors
while their long-term use is associated
with decreased dendritic reorganization
and spine density in the limbic regions
after initial increase and neurotoxicity in
amygdala structures.
44.
45. sex hormones seem to play their major neuro-modulatory action in early prepubertal life
with subsequent decrease in the neuronal sensitivity to their
actions with advancement of age.
◘ Sex HRT seems to be theoretically
beneficial but the translation of this
hypothesis to practice met a lot of
difficulties which made the use of
HRT in AD management still a
matter of skepticism.
46. ◘ The values of HRT are mainly dependent on the timing, dose and duration
of their application to the AD predisposed individual.
◘ Promising results were only attained on early starting of estrogen HRT at a
close menopause temporal proximity and any delayed administration may
even give counterproductive bad consequence.
◘ This time limit of proper HRT initiation resulted in introduction of the
term the critical window of intervention or the window of opportunity
which describes the time after which HRT become worthless.
47. sex hormones seem to play their major neuro-modulatory action in early prepubertal life
with subsequent decrease in the neuronal sensitivity to their actions with advancement of
age.
◘ HRT has not the same effect in all genotypes, but it is found to be more
beneficial in people with APOE-2 and APOE-3 genotypes than APOE-4.
◘ The protective effect of HRT is only achieved in long term users (> 10
years) while short term therapy had no AD preventive actions.
◘ Unfortunately, the need for long-term use of conventional HRT open a
new obstacle due to the high cardiovascular risks which in some instances
may overwhelm the anti-AD cognitive benefits.
48. sex hormones seem to play their major neuro-modulatory action in early prepubertal life
with subsequent decrease in the neuronal sensitivity to their actions with advancement of
age.
49.
50. ◘ Menopausal and andropausal gonadal sex
hormonal declines may be the trigger of
irreversible neuropathological changes
which latter on may progress to AD in
susceptible individuals.
51. ◘ Sex HRT seems to be theoretically
challenging in AD drug pipeline, but it
still facing a lot of obstacles which
need further works to introduce safe
and effective agents suitable for long-
term use started prior to the onset of
the window of opportunity.
52.
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