Cabellero - Amyloid-B & Tau Flashcards
(32 cards)
What is mild cognitive impairment (MCI) in the context of Alzheimer’s disease, and how does it progress?
Alzheimer’s disease is the most common form of dementia
Progresses over ~8 years from diagnosis to death (on average)
Death is typically due to loss of vital functions (e.g. swallowing, breathing), not memory loss
Mild Cognitive Impairment (MCI):
- Often the first clinical sign of Alzheimer’s disease
- Specifically affects declarative memory (recent events, names, appointments, conversations)
- People may compensate for a time, but MCI often progresses to more severe cognitive decline
What changes occur in the brain during the progression of Alzheimer’s disease?
Preclinical phase (~15 years before symptoms):
- No obvious memory or behavioural changes
- Brain structure appears normal on imaging
Mild Cognitive Impairment (MCI):
- Early signs of memory loss begin to appear
- Structural brain changes may be detectable (e.g. on MRI)
- Significant synapse loss, especially in the hippocampus
Severe Alzheimer’s disease:
- Extensive grey matter loss
- Brain shows visible shrinkage
Hippocampus involvement:
- The disease specifically affects declarative memory
- Damage mirrors the memory impairment seen in famous patient H.M., whose hippocampus and medial temporal lobes were removed
- The hippocampus is a key target of research due to its central role in memory and early vulnerability in Alzheimer’s
What pathological changes define Alzheimer’s disease in the brain?
Brain shrinkage occurs, especially in the hippocampus and cortex
Alzheimer’s disease is defined by the accumulation of abnormal protein clumps:
Extracellular:
- Amyloid-β plaques
- Found outside neurons
- Accumulate around blood vessel walls (cerebral amyloid angiopathy)
- Disrupt cell communication and trigger inflammation
Intracellular:
- Neurofibrillary tangles of hyperphosphorylated tau
- Tau becomes insoluble and accumulates in cell bodies
- Found inside neurons
- Disrupt cell transport and contribute to neuronal death
These changes lead to synapse loss, neuronal degeneration, and cognitive decline
What are the alzheimers disease risk factors?
Age
Lifestyle
- Diet
- Cardiovascular health
- Social factors
Clinical
- High blood pressure
- Diabetes
- Down syndrome
- Depression
Genetic
- APOE variants (modify AD risk)
Mutation
- Amyloid precursor protein (APP, from which ABeta is produced) causes AD. Although very rare.
What genes are associated with Alzheimer’s disease, and how do they vary in risk and population
High Risk, Rare (Causal):
- PSEN1, PSEN2, APP: Mutations in these genes can cause early-onset familial Alzheimer’s
Medium Risk, Rare:
- TREM2 :Rare in the population, but significantly increases risk
Common, Variable Risk (Late-onset Alzheimer’s):
- APOE4 (1 copy): Increases risk moderately
- APOE4 (2 copies): Significantly increases risk of Alzheimer’s, Dose-dependent effect
Common, Low Risk (Risk Modifiers):
Genes such as MS4A, CR1, PICALM, BIN1, CLU, CD2AP, CD33, EPHA1, ABCA7
- Common in the population
- Each confers a small increase in risk
Key takeaway:
- Gene impact is a spectrum — some rare genes cause Alzheimer’s directly, while others are common modifiers of risk
- APOE4 is the strongest genetic risk factor for late-onset Alzheimer’s
How does amyloid-β pathology develop in Alzheimer’s disease?
Amyloid-β (Aβ) is normally secreted as a soluble monomer
In Alzheimer’s, Aβ undergoes abnormal aggregation
Aggregation stages:
- Oligomers (small clusters)
- Protofibrils
- Fibrils
- Insoluble extracellular plaques
This process is called amyloidosis
Aggregated Aβ becomes misfolded, insoluble, and neurotoxic
Accumulated plaques disrupt cellular communication and trigger inflammation
How is amyloid-β generated from amyloid precursor protein (APP), and why is it important in Alzheimer’s disease?
APP is a transmembrane protein with:
- N-terminal extracellular domain
- C-terminal intracellular domain
Amyloid-β (Aβ) is produced through proteolytic cleavage of APP via two key enzymes:
- β-secretase (BACE1) → cleaves APP in the extracellular region
- γ-secretase → cleaves within the membrane, releasing amyloid-β
Presenilin-1 and Presenilin-2 are part of the γ-secretase complex
- Mutations in PSEN1, PSEN2, and APP are linked to familial (early-onset) Alzheimer’s disease
Misprocessing of APP → excessive Aβ production → aggregation into plaques → neurotoxicity
Therapeutic strategies include attempts to inhibit BACE1 or γ-secretase to reduce Aβ generation (several have been trialled)
What is the significance of the APP ‘London mutation’ in Alzheimer’s disease research?
Mutations in APP, PSEN1, and PSEN2 increase amyloid-β (Aβ) production
A key discovery was made by Sir John Hardy in 1992
- Identified a family with a mutation in the APP gene
- Mutation became known as the London mutation
- Linked to early-onset familial Alzheimer’s disease
The study supported the original amyloid cascade hypothesis, which proposed that Aβ accumulation causes Alzheimer’s
More recent research has refined the amyloid hypothesis, recognising it as part of a more complex disease process
How many mutations are known in the APP gene, and where do they tend to occur?
- There are more than 50 known mutations in the amyloid precursor protein (APP) gene
- These mutations are associated with early-onset Alzheimer’s disease
- Most occur near the sites of β-secretase and γ-secretase cleavage
What evidence from Down syndrome supports the role of APP and amyloid-β in Alzheimer’s disease?
- Down syndrome (trisomy 21) causes individuals to have three copies of chromosome 21
- The APP gene is located on chromosome 21
- This results in increased APP expression and higher Aβ accumulation
- People with Down syndrome often develop Alzheimer’s-like pathology if they live long enough
Supporting evidence: a Down syndrome patient missing the APP region of chromosome 21 did not develop Aβ pathology
What did the 2012 Icelandic study reveal about a protective APP mutation and Alzheimer’s disease?
- Researchers identified a rare APP mutation (A673T) in ~1 in 100 Icelanders
- Carriers of the mutation had better preserved cognition with age compared to the general population
- The mutation was shown to reduce amyloid-β production in vitro
- Compared with wild-type APP, cells expressing the A673T mutation released less Aβ into the media
- Supports the idea that lower amyloid-β levels protect against Alzheimer’s disease
- Contrasts with other APP mutations known to increase Aβ and promote pathology
What did early Alzheimer’s vaccine trials in the 2000s reveal about amyloid-β immunisation?
Researchers attempted active immunisation against amyloid-β to clear plaques from the brain
Patients were injected with a peptide vaccine to stimulate their immune system to attack Aβ
The trial was halted due to serious side effects, including brain inflammation (meningoencephalitis) and deaths
Post-mortem studies (including work from Southampton researchers) showed:
- Aβ plaques were removed in many vaccinated brains
- However, cognitive function did not improve — some patients still scored 0 on cognitive assessments despite plaque clearance
Key outcome:
- Clearing plaques in late-stage Alzheimer’s is not sufficient to rescue cognition
- Damage to the brain may already be irreversible at this stage
What is aducanumab, and what have we learned from its use in Alzheimer’s disease?
Aducanumab is a passive immunotherapy (antibody-based) targeting amyloid-β
Administered regularly (e.g. monthly) to clear Aβ plaques
Unlike older approaches, it is not an active vaccine, so its effects can be reversed if needed
Approved in a fast-tracked process for mild to moderate Alzheimer’s disease
Key lesson:
- Amyloid-β clearance alone is not sufficient to reverse or stop Alzheimer’s
- Amyloid-β may initiate the disease, but immune responses (e.g. microglia) also play major roles
- Future treatments may need to target multiple pathways, not just Aβ
What does population imaging data reveal about the timing of amyloid-β accumulation in Alzheimer’s disease?
Alzheimer’s is an age-related disease, with prevalence increasing significantly after ~age 70
Amyloid-β plaques begin accumulating up to 15 years before diagnosis
Imaging studies (e.g. PET scans) detect plaques in asymptomatic individuals starting in their 50s and 60s
This highlights a long preclinical window during which intervention may be most effective
Supports the view that treatment should begin before symptom onset, not after cognitive decline becomes evident
What does synapse loss tell us about early Alzheimer’s disease pathology?
Synaptic dysfunction and loss are likely early pathological events in Alzheimer’s
Research by Stephen Scheff analysed brains within 3 hours post-mortem for high accuracy
Studied brains from patients with:
- No cognitive impairment
- Mild cognitive impairment (MCI)
- Early Alzheimer’s disease
Findings:
- ~44% reduction in synapse density in the dentate gyrus of early Alzheimer’s patients
- Similar results in CA1 region of the hippocampus
- Synapse density correlated more strongly with cognition (MMSE scores) than amyloid plaques or tau tangles
Conclusion:
- Synaptic loss is a key early driver of cognitive decline and may precede plaque/tangle pathology
Benefits and drawbacks of studying AD in humans
Benefits:
- Direct patient studies (e.g. brain imaging, post-mortem pathology) offer valuable insights
- Show plaque accumulation, synapse loss, and link to cognitive decline
Drawbacks:
- Logistically and ethically difficult, especially for early or long-term study
Why do researchers use mouse models to study AD?
Mice are mammals with similar hippocampal structure and declarative memory
Allow controlled study of molecular mechanisms and gene interactions
Common tests: e.g. Morris Water Maze to assess memory
What are some common limitations of using mouse models to research AD?
Mice live ~2 years, can’t model the 15-year human disease progression
No mouse model fully recapitulates Alzheimer’s pathology
Most APP mutation models show amyloid plaques, but few show tangles unless tau mutations are also introduced
Useful for studying specific aspects, not complete disease progression
What experimental models are used to study Alzheimer’s disease, and what are their applications?
Mouse models:
- Often involve transgenic expression of mutant APP or tau
- Allow study of pathology, memory (e.g. via behaviour tests), and cellular mechanisms
- Can apply exogenous amyloid-β (synthetic or patient-derived) to observe neuronal effects
- Useful for short-term studies (hours to weeks)
In vitro models:
- Use mouse primary neurons, immortalised cell lines, or human iPSC-derived neurons
- Enable precise control over environment and timing
- Help dissect molecular pathways
Ex vivo brain slices:
- Can be taken from mouse models or rare cases of resected human brain tissue
- Allow real-time study of neuronal responses to amyloid-β
Key point:
- Each model offers specific insights, but none fully replicates Alzheimer’s disease progression in humans
What is a key issue with using amyloid-β in Alzheimer’s disease research models?
Amyloid-β exists in multiple conformations:
- Soluble monomers, dimers, oligomers, protofibrils, fibrils, and plaques
Experimental studies often use:
- Transgenic expression (in vivo)
- Exogenous application (in vitro or ex vivo)
Key challenge:
- Lack of standardisation in how Aβ is prepared and applied
- Leads to variability in results across studies
- Mixed forms of Aβ at high concentrations consistently show high toxicity to neurons
Conclusion:
- Understanding Aβ toxicity requires precise control and definition of its form
- Variability in Aβ conformations makes comparison between studies difficult
How are transgenic mouse models used to study amyloid-β accumulation in Alzheimer’s disease?
Researchers can insert human familial Alzheimer’s disease APP mutations into mice
This causes hyperaccumulation of amyloid-β in the mouse brain
Plaques are visualised using silver staining, showing extracellular Aβ deposition
Studies compare plaque development in mice (3–9 months) to human Alzheimer’s brain stages
Example model: Line 102 mice
- Allows transgene to be switched on or off
- Enables controlled studies of Aβ expression effects over time
What is the Morris Water Maze and how is it used to assess memory in Alzheimer’s research?
- The Morris Water Maze tests spatial learning and memory in mice
- Mice are placed in a circular tank of opaque water
- A hidden platform is placed just below the water surface
- Mice must learn the platform’s location using spatial cues
- Over repeated trials, healthy mice learn to swim directly to the platform
- Used to assess the impact of Alzheimer’s-related pathology (e.g. amyloid-β) on memory performance
What does the Morris Water Maze reveal about memory in APP transgenic mice?
Wild-type mice (normal APP gene):
- Learn to find the hidden platform
- Show targeted searching in the correct quadrant
- High platform crossing score indicates intact spatial memory
Transgenic mice expressing mutant human APP:
- Show impaired memory
- Display random searching across all quadrants
- No preference for platform location → no memory retention
Conclusion:
- Mutant APP expression disrupts spatial memory, consistent with Alzheimer’s-like cognitive deficits
What do memory and synaptic studies in APP transgenic mice reveal about the role of amyloid-β?
Behavioural evidence (Morris Water Maze):
- Wild-type mice: learn and recall platform location → normal memory
- Mutant APP mice: random searching, indicating memory impairment
Synaptic plasticity (brain slice recordings):
- Mutant APP mice show impaired synaptic transmission in hippocampal slices
- Deficits present before visible plaque formation
Key insight:
- Amyloid-β itself, not just plaques, causes early synaptic dysfunction
- This challenges older views that plaques cause damage primarily by physically disrupting tissue
- Shows soluble Aβ can impair neural circuits before structural pathology appears
