AD and dementia Flashcards
Outline impact of dementia on society
Dementia is most common condition resulting from neurodegeneration: economic cost of $818 billion.
65% of people living with dementia are women.
Prevalence of dementia
Age is a major risk factor of dementia: prevalnce doubles every 5 years.
Estimated prevalnce is 60-64 years = 0.9%
95yrs and older = 41.1%
Dementia verus normal lapses of memory
Dementia: not recognising family member, forgetting to serve meal just cooked, not recognising numbers, dramatic change in personality.
Normal lapses of memory: forgetting a name, leaving the kettle on, losing things, gradual changes with ageing.
How to test for dementia
Mini Mental State Examination(MMSE): ask date/location, recall of objects, simple calculations.
When asked to draw a clock face: will completely forget or draw completely wrong.
Does MCI lead to dementia
MIld cognitive impairment can sometimes indicate prodromal AD (period between initial AD symptoms and full development of disease).
For o.
thers, this will not progress beyond MCI.
State different types of dementia
1) Alzheimer’s disease: over 50%
2) Vascular dementia: 20%
3) Dementia with Lewy body: 15%
4) Frontotemporal dementia (FTD): 2%
5) Rare causes: Parkinson’s disease dementia, Huntington’s disease, prion disease, others.
State risk factors of dementia
Age
Genetics: most cases are sporadic but rarely can be inherited (APP mutations presenilin genes).
Cardiovascular disease: smoking and diabetes increase risk where exercise decreases risk.
Depression
Head trauma
State physiological role of alphaBeta and how it plays a part in pathology of AD
ABeta monomer - physiological: synaptic function, BBB protection, antimicrobial effect.
ABeta oligomers - pathological: synaptic damage, microglia activation, Ca2+ dyshomeostasis.
State physiological role of tau and how it plays a part in pathology of AD
tau monomer - : DNA protection, microtubule stabilisation, dendritic development.
tau oligomers - pathological: disturbed neural circuits, microtubule degradation, synaptic loss
Outline the non-amyloidogenic pathway and state role
This is the ‘good’ pathway: produces sAPPalpha (neuronal survival, neurite outgrowth, neural stem cell proliferation, enhances LTP).
sAPP is created by APP being cleaved by alpha-secretase (ADAM)
* Gamma-secretase then goes on to produce P3 and AICD from other part of APP that have no known role.
Outline the amyloidogenic pathway and state role
This is the ‘bad’ pathway: produces sAPPBeta which lacks the neuroprotective effects of sAPPAlpha, ABeta protein that forms plaques.
Beta-secretase (BACE1): sAPPBeta and other part(C99). Gamma-secretase then goes on to cleave left over into ABeta and AICD.
ABeta: different lengths created with 42 amino acid length being the worst.
AICD: translocated to nucleus and activates transcription of target genes such as GSK3-Beta
Why is BACE1 a target of research and what did research find?
BACE1: if this enzyme doesn’t exist = ABeta plaques would not form.
Unfortunately, BACE1 KO causes hypomyelination (including the optic nerve) and frequent epileptic seizures.
Outline how ABeta aggregates to form plaques
Secondary structure: is predominantly alpha-helical but global conformational rearrangement and formation of beta-sheet structures (similar to prion) by fibrillization.
APP forms monomers, dimers, oligomers, protofibrils, fibrils and amyloid plaques.
Outline progression of AmyloidBeta plaque deposition.
Neocortex (bar M1), allocortical, subcortical structures as the disease progresses.
This revealed from PET scans and postmortems.
Outline targeted treatment of AD via AmyloidBeta
Beta-secretase inhibitors, active and passive immunisation to try and clear the plaques and gamma-secretase inhibitors. All failed to pass clinical trial due to severe side effects and lack of positive side effects bar aducanumab.
Aducanumab: antibody therapy that targets amyloidBeta. This is controversial…
* Reduced visible plaques in brain (surrogate outcome) = no patient benefit.
* No noticeable effect on patient outcomes (quality of life or dementia).
Serious adverse effects are common: edema and hemorrhage in the brain which causes dizziness, headache, nausea which can lead to hospitalisation and long-term impairment.
Overall, can conclude that ABeta plaques alone don’t cause AD.
Outline how neurofibrillary tau tangles form
Tau proteins are microtubule-associated proteins that promote formation and stability of the microtubule network. When not bound to microtubules they are prone to degradation and phosphorylation.
When tau becomes hyperphosphorylated it becomes insoluble and prone to associate with other molecules. There are 6 different isoforms of tau, isoforms with three micro-tubule repeats are not as good at promoting stability and therefore more likely to form tangles.
NFTs are composed of two types of fibrils: paired helical filaments and straight filaments (SFs) but in AD, PHFs predominate (90%). The number of neurofibrillary tangles is a pathologic marker of the severity of Alzheimer’s disease.
Enzymes that add and those that remove phosphate residues regulate the extent of tau phosphorylation.
Outline targeted treatment of AD through tau proteins.
Anti-tau vaccines, monoclonal antibodies, microtubule stabilisers, GSK3-Beta inhibitors etc.
Similar to APP, antibodies successfully decreased tangles but had no effect on patient outcomes.
Outline synapse loss in Ad vs normal ageing
Synapse loss occurs with ageing but advancing AD synapses are disproportionately lost relative to neurons.
* reduction in dendritic branch length and arbor complexicity .
* reductions in synaptic vesicle trafficking (alters normal synaptic transmission).
* Down regulation of post-synaptic proteins like PSD-95 and drebrin.
Synapse loss and cognitive deficits
Synapse loss in CA1 strongest correlate for cognitive deficit as tested by MMSE.
Outline animal model that suggests failure of synaptic plasticity involved in AD
During hibernation due to cold temp synapses are pruned.
In normal animals when return to warmer climate they get synapses back, this does not occur in AD animal models.
Implies failure of regenerative synaptic plasticity = when gene LV-RBM3 (neuroprotective) overexpressed the ability to regenerate synapses comes back, also animals survive longer.
NB: same effect seen in prion disease and same overexpression of LV-RBM3 also allows regeneration of synapses.
Potential for drugs that act like LV-RMB3 therapeutically.
Outline role of microglia in AD
Microglia have 2 roles in Alzheimer’s Disease which change as the disease progresses
In early disease (M2)– neuroprotective as it aims to clear cell debris, phagocytose dead cells, and release neurotrophic factors.
In later disease (M1)– persistence of damaging stimuli means microglia are chronically activated & release inflammatory cytokines that drive neurotoxicity and neurodegeneration.
Looking at shifting activation to M2.
Outline role of astrocytes in AD
There are 2 types of Astrocytes with contrasting roles in AD depending on which intracellular signalling pathways they activate (Liddelow and Barres, 2017a).
A1 astrocytes are neurotoxic – they are stimulated by activated microglia release of interlukin-1 alpha (IL-1α), complement component 1q (C1q) and TNF-α. They can then activate β & γ secretase activity, generating astrocyte derived Amyloid β. They can also cause secretion of neurotoxins, loss of synaptogenesis and neuronal death
A2 astrocytes are neuroprotective – they upregulate several neuroprotective factors that promote synaptic repair, growth, and survival of neurons.
Shifting activation to A2.
Correlation of Apolipoprotein-E to AD.
APOE ε4 allele is one of the highest risk factors for AD
Major transporter for lipids, cholesterol and fat-soluble vitamins. Produced in liver and by astrocytes and microglia
Can cause clumping of fibrils into plaques
Connection to bilingualism and AD
Voits et al., 2020
Delayed onset AD in bilingual individuals, thought to be due to additional reinforcement that allows brain to cope for longer with neurodegeneration.
CR: cognitive reserve, greater cognitive compensatory ability.
BR: brain reserve, progressive structural reinforcement of the brain in both grey and white matter.
Oscillations in AD
Traikapi and Konstantinou, 2021
Gamma: implications in memory and cognitive function, aberrant gamma waves observed in human AD patients.
Auditory and visual stimulation to restore gamma oscillations attenuated AD pathology in mice models.
TMS 40hz prevents grey matter loss.
NB: some studies reported increased gamma in AD.
Link between APOE and AD
Different isotopes have diff risk.
4) strongest genetic risk factor for sporadic AD.
2) strongest genetic protective factor against sporadic AD: less widespread ABeta plaques and neurofibrillatory tangles in autopsy cohort.
Serrano-Pozo et al., 2021
Pathophysiological mechanisms of APOE
ABeta: contains APOE, interacts with plaques and promotes aggregation and deposition in insoluble fibrillar deposits. 4 specifically inhibits enzymatic degradation of ABeta.
Tau: no direct interaction but downstream pathology impacted. 4 promotes tau induced neurodegeneration and atropy.
Glia: microglia from APOE is proinflammatory.
BBB: increases permeability in ABeta dependent manner.
Serrano-Pozo et al., 2021
Therapeutics targetting APOE for AD
Blocking ABeta and APOE interaction.
Switching isoforms: CRISPR to switch alleles successful in neuronal pluripotent cells.
Serrano-Pozo et al., 2021
More recent AD theory
Inside neuron:
1) lysosomes make autolysosomes that don’t break down waste.
2) Autolysosomes accumulate waste and increase in number.
3) Overfilled autolysosomes bulge out of cell mem. Near nucleus create dense core of amyloid-beta fibrils.
4) Autolysosomes rupture and release toxins that kill neurons.
Outside neuron:
1) cell mem bursts, spills toxins into space between neurons.
2) microglia, the immune system cells try to clean up debris.
Outline remniscence therapy
Berg-Weger and Stewart, 2017
Encourages patients to talk about past memories (find it harder to talk about recent) therefore decreased cognitice demand.
* improves mood.
* mixed result on cognitive benefit.
Outline validation therapy
Berg-Weger and Stewart, 2017
Individuals with dementia present with confusion to escape the reality of boredom, stress loneliness. Thought to be beneficial only for mild to moderate and focused on validating feelings not real facts.
- alleviates stress
- decreases emotional disturbances.
Outline reality orientation
Berg-Weger and Stewart, 2017
Facilitators present info through games, puzzles etc.
* cognitive and behavioural benefits.
Outline cognitive stimulation therapy
Berg-Weger and Stewart, 2017
Given tasks in a social setting.
* improves processing and recall.
* reduction in behavioural issues.
Outline glial targeted strategies for treating AD
Hussain et al., 2018
Microglia detected up to 15 years before symptom onset. Activated microglia undergo morphological changes. Imperative to early detection of HD.
Microglia needed so therefore cannot just shut down activation. Instead proposed shift from M1 activation to M2.
