Mudher - Alzheimers

Question 1

What is alzheimers disease characterised by?

Answer 1

Progressive neuronal loss

Neurodegeneration due to cell death

Lots of cell death in frontal and parietal cortex

Major cell death in temporal lobe

Question 2

What is important about cell death in the temporal lobe?

Answer 2

The temporal lobe, especially the hippocampus and entorhinal cortex, is critical for declarative memory

The circuits that deal with short term processing live in the temporal lobe

This leads to hallmark symptoms such as:

• Memory loss
• Difficulty forming new memories
• Getting lost or confused about time and place

Neuroimaging and post-mortem studies show early shrinkage and atrophy in the temporal lobe

Question 3

Why are patients initial symptoms short term memory loss rather than long term memory loss?

Answer 3

It is thought disease begins in the temporal lobe, before spreading via neuro anatomical pathways to the parietal lobe

Temporal lobe = short term memory
Parietal lobe = long term memory

Because the disease starts in the temporal lobe short term memory is affected first, after disease spreads to the parietal lobe long term memory decline occurs too

Question 4

What are the two drivers of alzheimers disease at a biological level?

Answer 4

Plaques:

• Caused by amyloid-β (Aβ) misfolding and aggregating into extracellular plaques
• These accumulate outside neurons in the - extracellular space, especially in the cortex and hippocampus
• Thought to disrupt synaptic communication and trigger downstream pathological processes

Neurofibrillary tangles (NFTs):

• Caused by tau protein becoming hyperphosphorylated, misfolding, and aggregating
• Form intracellular tangles inside neurons
• Associated with cytoskeletal breakdown, neuronal dysfunction, and cell death

Question 5

How is Tau abnormal in AD and all other taupathies?

Answer 5

In ALL tauopathies, the Tau protein is aggregated

In ALL tauopathies, the Tau is hyperphosphorylated

Some tauopathies present with abnormally expressed Tau (abnormal levels of tau isoforms)

The diseases are only different because the aggregated Tau is found in different regions of the brain –> therefore affecting different circuits

Question 6

How does abnormal tau expression contribute to tauopathies via 3R and 4R tau isoforms?

Answer 6

Tau protein is normally expressed in multiple isoforms due to alternative splicing

These isoforms differ by the number of microtubule-binding repeats:

• 3-repeat (3R) tau
• 4-repeat (4R) tau

In healthy adult human brains, there’s a balanced 1:1 ratio of 3R and 4R tau

In certain tauopathies (e.g. Pick’s disease, progressive supranuclear palsy, corticobasal degeneration):

• This balance is disrupted, leading to predominance of either 3R or 4R tau
• Resulting isoform accumulation contributes to tau misfolding, aggregation, and neurodegeneration

Conclusion:

• Abnormal splicing and isoform ratios of tau are key contributors to disease-specific pathology in non-Alzheimer’s tauopathies

Question 7

What does phosphorylation generally do?

Answer 7

Most understand it alters activation energy

More unknown is that it also serves as a marker for degredation

Proteins that are phosphorylated are marked for degredation by the ubiquitin proteosome system

Question 8

What is the prevelance of normal tau phosphorylation?

Answer 8

In a healthy brain, only 5% of tau is every phosphorylated

There are 76 different sites on tau that are able to be phosphorylated

Question 9

What is the prevelance of tau phosphorylation in alzheimers disease

Answer 9

100% of tau is phosphorylated in the alzheimers brain

Every single tau molecule is hyperphosphorylated

Question 10

Why does western blotting tau isoforms in an alzheimers disease patient look like there are only 3 isoforms present?

Answer 10

Due to hyperphosphorylation, tau aggregates run slower on a western blot, making all 6 isoforms run slower giving the view that there are less isoforms

This is called retarded gel motility

Question 11

How did they prove that the tau aggregate bands on the western blot were actually all 6 isoforms aggregated due to phosphorylation and not just 3 isoforms

Answer 11

They incubated the brain homogenous with a phosophatase to remove the phosphate groups, and ran it again on western blot to prove there are 6 bands/isoforms present

Question 12

What is picks disease?

Answer 12

It is a tauopathie

It results from 3R tau isoform aggregation

Leads to generation of pick bodies (not tangles)

Mainly affects regions in the frontal lobe (planning, decision-making, problem-solving, motor control, speech production, aspects of personality and emotional regulation)

Symptoms:
- Behavioural
- Personality
- Disinhibition (impulsive behaviours)
- Language deficits

Question 13

What is progressive supranuclear palsy?

Answer 13

It is a tauopathie

It results from 4R isoform aggregation

Tau aggregates consist of:
- Classic NFT
- Globus NFT (in oligodendrocytes)
- Astrocytic tufts (in astrocytes)
- PSP fold

Located mostly in:
- Subthalmic nucleus
- Substantia nigra

Symptoms:
- Early falls
- Balance/postural abnormalities
- Resting tremor
- Shuffling gait
- Some cognitive / memory impairments

Question 14

What is it that determines where tau aggregates? Why does tau aggregate in different regions of the brain in differing diseases?

Answer 14

Not entirely known, few ideas

Local environments in differing brain regions could differ, leading to aggregation in some areas and not others due to protein-environment interactions

Potential splicing differences in differing brain regions

Different diseases in brain regions result in different folds of the tau protein, each tau aggregate in each disease is folded in a different manner:
- AD = Alzheimers fold
- PD = PiD fold (picks fold)
- PSP = PSP fold

These different foldings are called tau ‘conformers’

Potentially chaperone proteins, different regions may have differnet chaperone proteins that cause the tau to fold in differnet ways

Question 15

How has our understanding of tau’s role in Alzheimer’s disease evolved over time?

Answer 15

Historically:

• Tau tangles were seen as a secondary consequence of neuronal degeneration
• Focus was on amyloid-β plaques as the primary cause
• No known tau gene mutations in Alzheimer’s supported this view

New understanding:

• Tau mutations are now known to cause primary tauopathies (e.g. frontotemporal dementia)
• These tau pathologies are strikingly similar to those in Alzheimer’s disease
• Hyperphosphorylated, aggregated tau alone is enough to drive neurodegeneration
• The presence of tau tangles, not amyloid, correlates best with cognitive decline

Analogy:

• Amyloid-β = gun, tau = bullet
• The bullet (tau pathology) is what causes the damage, regardless of who pulls the trigger

Question 16

What is the normal physiological role of tau protein in the brain?

Answer 16

Tau is a microtubule-associated protein predominantly found in neurons

Tau binds directly to microtubules

It stabilises microtubules, which are essential for:

• Axonal transport of nutrients, organelles, and signalling molecules
• Maintaining neuronal structure and polarity

Tau is regulated by phosphorylation under normal conditions:

• This modulates its binding to microtubules
• Dynamic phosphorylation allows flexibility in microtubule dynamics

Tau is mostly unstructured (intrinsically disordered) under basal conditions

• This allows it to interact with multiple partners in the cytoskeleton

Question 17

How does abnormal tau affect normal tau biological functions?

Answer 17

1. Reduces its ability to bind to microtubules
2. Microtubule tracks collapse
3. Axonal transport is compromised
4. Synaptic activity is disrupted

Question 18

How was the tau-MT hypothesis tested?

Answer 18

Drosophila models microtubule-tau binding:
- Used p-tau to show that there is less microtubule binded tau in models with hyperphosphorylation of tau compared to controls with normal tau

Electron Microscopy:
- Shows breakdown of microtubule structure compared to controls

Tagged transport proteins with green flourescence to visualise transport pathways:
- Control had green flourescence along entire axon, proving strong microtubule transport
- Hyperphosphorylated model shows extreme disruption to microtubule transport

Electrophysiology to prove degredation of synapse
- Record excitatory potential at muscle synpase, reduce potential shows damage to microtubules and to synapse itself
- Can also look directly at the synapse to see the shape, healthy synapse have a specific shape and damaged ones are misformed (30% smaller and mishaped)

Maggot behaviour testing, to test function of motor neurones with hyperphosphorylation
- Maggots with hyperphosphorylation took longer to complete designated climb than control maggots
- Larvae took 3x as long to turn themselves the rigth way up when hyperphosphorylated

Question 19

How can we counter abnormal tau mediated neuronal disfunction?

Answer 19

1. Reduce tau phosphorylation (kinase inhibitors)
2. Microtubule stabilising agent

Question 19

What is a potential microtubule stabilising agent?

Answer 19

Chemotherapy

Drug called NAP that stabilises microtubules in cancerous cells has also been shown to work in alzheimers patients.

NAP shows a remarkable rescue of microtubule structure after only 24 hours

It has also been shown that when microtubules are put back together there is rescue in axonal transport mechanisms

This results in improved synaptic function

Question 20

Why when tau is knocked out in mice, do we not see loss of function?

Answer 20

This is because of complimentary mechanisms of the cells

Proteins that have similar functions of tau will be upregulated in situations where tau is knocked out

Question 21

What is the normal structural nature of wild-type tau?

Answer 21

Intrinsically disordered protein

Lacks secondary structure

Flexible, unstructured conformation

Question 22

What structural change occurs when tau becomes pathological?

Answer 22

Acquires a specific, stable conformation

Conformation varies by tauopathy (e.g., Alzheimer’s, Pick’s, PSP)

May involve phosphorylation and aggregation

Question 23

How many phosphorylation sites are found on the tau molecule?

Answer 23

76 phosphorylation sites

Question 24

What is the hypothesised link between phosphorylation and misfolding in tau?

Answer 24

Phosphorylation introduces negative charges Causes attraction to positively charged regions Induces folding that exposes sticky/aggregation-prone domains

Question 25

How does phosphorylation make tau more aggregation-prone?

Answer 25

Structural changes from phosphorylation can expose sticky regions (like microtubule-binding domains), facilitating aggregation.

Question 26

What does “seed competent” mean in the context of tau pathology?

Answer 26

A tau molecule is seed competent if it can: Induce aggregation of other tau molecules, Propagate misfolded structure to normal tau.

Question 27

How might phosphorylation promote further phosphorylation?

Answer 27

Initial phosphorylation may expose cryptic sites, increasing kinase access. Like oxygen binding to hemoglobin, this creates a cooperative effect.

Question 28

What is the hypothetical cascade of phosphorylation and aggregation in tau?

Answer 28

Initial phosphorylation → Misfolding → Exposure of aggregation sites → Further phosphorylation → Aggregation.

Question 29

What are tau oligomers and how do they form?

Answer 29

Oligomers are small aggregates (3–15 tau units) of misfolded tau. They precede the formation of larger filaments in Alzheimer's disease

Question 30

What are filamentous tau structures and their impact?

Answer 30

Filaments are large aggregated tau assemblies found in Alzheimer’s. They physically disrupt cell function, potentially "squeezing the life out of the cell."

Question 31

What major debate exists regarding tau toxicity?

Answer 31

Whether tau oligomers or filaments are more toxic. Many researchers now believe oligomers are more toxic, and filaments are protective or inert.

Question 32

How can animal models help determine tau toxicity?

Answer 32

Transgenic models allow expression of human tau, track its progression from monomer → oligomer → filament. Behavioral assays (e.g. Morris water maze, fly climbing assays) can measure dysfunction onset.

Question 33

What key fly model assay is used to assess neurodegeneration?

Answer 33

Climbing assay: 50 flies are knocked to the bottom of a vial, and their climbing ability is tested. Climbing deficits indicate neurological dysfunction.

Question 34

What did animal experiments reveal about tau species toxicity?

Answer 34

Eliminating tau expression reversed cognitive deficits, despite the presence of filaments. Suggests oligomers, not filaments, cause the toxicity.

Question 35

What unintended effect can anti-aggregation drugs have?

Answer 35

Some drugs break filaments into oligomers, potentially worsening symptoms by increasing toxic species.

Question 36

What does aggregation-dependent toxicity imply?

Answer 36

Tau must aggregate to form toxic oligomers, which then lead to oxidative stress, apoptosis, and nuclear deficits.

Question 37

How can pathological tau influence wild-type tau?

Answer 37

Misfolded tau can interact with wild-type tau, converting it into pathological tau via seeding.

Question 38

What does “prion-like” mean in the context of tau?

Answer 38

Misfolded tau acts similarly to prions: - Converts normal tau, - Spreads trans-synaptically, - Propagates throughout the brain.

Question 39

What historical disease illustrates prion-like spread?

Answer 39

Mad cow disease (BSE) and CJD involve

Question 40

Which tau species are more toxic: oligomers or filaments?

Answer 40

Oligomers are believed to be more toxic. Filaments may serve as a cellular strategy to sequester toxic species, making them less harmful.

Question 41

What evidence supports that oligomers are more toxic than filaments?

Answer 41

In transgenic mouse and fly models, eliminating oligomers restores memory even if filaments remain. Breaking up filaments into oligomers worsens symptoms.

Question 42

How can animal models help determine the most toxic tau species?

Answer 42

Express tau in transgenic animals and track behavioural decline (e.g., maze tests or fly climbing assays). Correlate the timing of deficits with presence of oligomers vs. filaments.

Question 43

What are common behavioural tests used in tauopathy models?

Answer 43

Rodents: Morris water maze, memory and learning tests. Fruit flies: climbing assays after knocking them to the vial bottom.

Question 44

What are potential consequences of breaking up tau filaments with drugs?

Answer 44

Drugs that disrupt filaments may release toxic oligomers, worsening cognitive deficits.

Question 45

What did studies show about anti-aggregation drugs in fruit fly models?

Answer 45

Disrupting tau filaments in previously normal flies caused new memory deficits, confirming filament disaggregation is harmful.

Question 46

What cellular stresses can tau oligomers induce?

Answer 46

Tau oligomers are linked to: - Oxidative stress, - Apoptosis, - Nuclear dysfunction.

Question 47

What is unexpected about tau’s role in the nucleus?

Answer 47

Although considered an axonal protein, tau has nuclear functions that are disrupted by oligomer formation.

Question 48

Why is aggregation essential to tau toxicity?

Answer 48

Aggregation is required to form toxic oligomers that drive oxidative stress, apoptosis, and nuclear deficits.

Question 49

How does toxic tau gain the ability to spread pathology?

Answer 49

Toxic tau can interact with wild-type tau and convert it to misfolded form — a prion-like mechanism.

Question 50

What is prion-like behaviour in tau?

Answer 50

Misfolded tau can replicate its structure by templating wild-type tau and spreading through synaptic connections.

Question 51

How did mad cow disease demonstrate protein spread through ecosystems?

Answer 51

Cows fed infected meat acquired prions, which spread to humans via food, highlighting protein-based transmission.

Question 52

What is the clinical significance of tau’s prion-like behaviour?

Answer 52

It helps explain the progression of Alzheimer’s: pathology starts locally and spreads anatomically across brain regions.

Question 53

Where does Alzheimer’s tau pathology typically begin?

Answer 53

In the entorhinal cortex, a region behind the ears involved in memory and learning.

Question 54

How does the spread of tau pathology relate to symptoms?

Answer 54

As pathology spreads to connected regions, patients show progressive cognitive and behavioural symptoms specific to those regions.

Question 55

What is the modern interpretation of Braak staging?

Answer 55

Pathology doesn’t randomly affect regions — it spreads through anatomically connected circuits.

Question 56

What type of evidence would support anatomical spread of tau?

Answer 56

Evidence that severing a brain connection prevents pathology from reaching connected areas — as shown in a case study of a tumour patient.

Question 57

What real-life case supported anatomical spread of tau pathology?

Answer 57

A woman with Alzheimer’s had no tau pathology in a frontal region that had been disconnected from the temporal lobe during tumour removal 20 years prior.

Question 58

What did this tumour case demonstrate about tau pathology?

Answer 58

Severing the connection between brain regions stopped the spread of tau pathology to anatomically downstream areas.

Question 59

What must be proven to confirm prion-like behaviour in tau?

Answer 59

That misfolded tau can convert wild-type tau in vivo and spread through connected circuits.

Question 60

What was the first in vivo demonstration of tau seeding?

Answer 60

A 2009 study injected tau from a mutant mouse (P301S) into a wild-type tau mouse, which then developed tau pathology.

Question 61

What mutation does the P301S mouse model carry?

Answer 61

The P301S mutation in tau, which causes aggressive frontotemporal dementia and promotes fast tau aggregation.

Question 62

How quickly do P301S mice develop tangles?

Answer 62

They develop tangles rapidly, unlike wild-type tau mice, which take up to two years to show pathology.

Question 63

What happened when P301S tau brain homogenate was injected into wild-type tau mice?

Answer 63

The wild-type mice developed phosphorylated, aggregated tau, showing seeding and conversion.

Question 64

What control was necessary in the tau seeding injection experiment?

Answer 64

Injection of brain homogenate from a non-pathological mouse, to confirm seeding — not injection stress — caused pathology.

Question 65

What key finding came from the tau injection experiment?

Answer 65

Abnormal tau can convert normal tau to misfolded form in vivo — definitive proof of seed competency.

Question 66

What is templated seeding in tau pathology?

Answer 66

When abnormal tau not only causes aggregation of wild-type tau but converts it to the same conformation as the original seed.

Question 67

Why does templated seeding matter in tauopathies?

Answer 67

It explains why different tauopathies (AD, PSP, Pick’s) show distinct tau conformations — the seed dictates the structure.

Question 68

How was templated seeding experimentally confirmed?

Answer 68

Wild-type tau mice were injected with brain homogenate from different tauopathy patients (AD, PSP, Pick’s), and formed matching tau structures.

Question 69

What did the templated seeding experiments prove?

Answer 69

Tau from each disease preserved its structural signature in the recipient, confirming strain-specific propagation.

Question 70

What term is used to describe different tau structures in tauopathies?

Answer 70

Conformers or strains — these are unique misfolded tau shapes, akin to prion strains.

Question 71

What is the clinical implication of tau strains?

Answer 71

Each tauopathy might require disease-specific therapies targeting its unique conformer.

Question 72

Could tau conformers be used therapeutically?

Answer 72

In theory, non-toxic tau conformers might be used to displace or outcompete toxic strains — though this remains speculative.

Question 73

What is the limitation of using non-toxic tau conformers therapeutically?

Answer 73

They may still impair tau’s physiological role, such as microtubule binding — leading to loss-of-function effects.

Question 74

What does tau propagation require beyond templated seeding?

Answer 74

It must also spread through anatomical circuits, not just convert tau locally.

Question 75

What are two key steps in tau prion-like behaviour?

Answer 75

Seed competency: Misfolded tau converts wild-type tau. Trans-synaptic propagation: Tau spreads across connected neurones.

Question 76

How was trans-synaptic spread proven in cell culture?

Answer 76

In microfluidic devices, tau with a fluorescent tag moved from pre- to post-synaptic compartments across axons.

Question 77

What are microfluidic devices used for in tau research?

Answer 77

To simulate neuronal circuits in vitro, allowing precise observation of tau movement and conversion between cells.

Question 78

What did tagged mutant tau show in microfluidic experiments?

Answer 78

It spread efficiently across synapses, far more than wild-type tau, confirming enhanced transmissibility of misfolded tau.

Question 79

How was tau propagation tested in live animal brains?

Answer 79

Misfolded tau was injected into a specific brain region, and tau pathology was later found in anatomically connected areas.

Question 80

What did hippocampal tau injection studies show?

Answer 80

Injecting tau into CA1 of the hippocampus caused pathology to spread to CA3, dentate gyrus, and contralateral regions over time.

Question 81

How does tau spread to contralateral brain regions?

Answer 81

Via anatomical connections between hemispheres; injected tau in one hemisphere spreads to connected regions on the opposite side.

Question 82

What role do glial cells play in tau propagation?

Answer 82

Microglia and astrocytes may contribute to tau uptake, clearance, or spread between neurons.

Question 83

How are astrocytes and microglia metaphorically described in the brain?

Answer 83

As parents: astrocytes provide nutritive support, microglia offer protection and debris clearance.

Question 84

What happens if glial cells are dysfunctional in tauopathies?

Answer 84

Inefficient clearance of misfolded tau may result in accidental redistribution and propagation of seeds.

Question 85

How is microglial dysfunction likened to waste collection?

Answer 85

Microglia are like overloaded garbage trucks: they collect misfolded tau but leak it into neighbouring cells, spreading toxicity.

Question 86

What evidence supports microglial involvement in tau spread?

Answer 86

Experiments show that microglia internalise tau, and may later release it, enhancing intercellular transfer.

Question 87

How does glial dysfunction potentially affect susceptibility to tauopathies?

Answer 87

People with inefficient immune/glial responses may fail to contain early tau pathology, leading to wider spread.

Question 88

What is the 100+ Study in Amsterdam?

Answer 88

A study of centenarians (people aged 100+) who remain cognitively healthy, investigating genetic protective factors.

Question 89

What protective traits were identified in the 100+ Study?

Answer 89

Upregulation of genes involved in: Autophagy, Microglial immune activity, Cytoskeletal integrity.

Question 90

What is the suggested role of enhanced microglial function in longevity?

Answer 90

Efficient debris clearance may prevent tau propagation, offering protection from tauopathies.

Question 91

What is the analogy of microglia as “security guards”?

Answer 91

Microglia detect and clear misfolded tau early — if efficient, they can contain pathology before it spreads.

Question 92

What are current questions in tau propagation research?

Answer 92

How tau exits and enters neurons. Which receptors and transporters are involved. Whether the mechanism is direct or glia-mediated.

Question 93

What are proposed routes of tau exit from neurons?

Answer 93

Exosomes, Microvesicles, Passive release, Direct secretion.

Question 94

What are proposed routes of tau entry into recipient neurons?

Answer 94

Via endocytosis, Heparan sulfate proteoglycans (HSPGs), Or nanotubules (direct bridges between neurons).

Question 95

What are nanotubules and how might they relate to tau?

Answer 95

Tiny, tubular structures that may form direct bridges between neurons — potential pathways for tau transfer.

Question 96

What is a major experimental challenge regarding nanotubules?

Answer 96

They are difficult to observe in vivo; most evidence comes from cell culture models.

Question 97

What experiment proved HSPGs are involved in tau entry?

Answer 97

Treating cells with heparinase, which digests HSPGs, reduced tau uptake — published in Science.

Question 98

Why can’t HSPGs be directly targeted in therapy despite their role in tau uptake?

Answer 98

HSPGs have essential functions in cell signalling and structure; inhibiting them would cause harmful side effects

Question 99

What is the challenge in targeting kinases like GSK3β for tau therapy?

Answer 99

Kinases are not tau-specific — inhibiting them may disrupt many physiological processes across the body.

Question 100

Why did GSK3β inhibitors fail in clinical trials?

Answer 100

Despite reducing tau phosphorylation, they caused widespread side effects due to non-specific kinase inhibition.

Question 101

What does the failure of kinase inhibitors highlight about tau therapies?

Answer 101

Therapies must be highly specific; broad kinase inhibition can cause system-wide dysfunction.

Question 102

What determines whether a recipient neuron is damaged by tau seeds?

Answer 102

Possibly the amount of wild-type tau converted, leading to: Loss of normal function, Gain of toxic functions over time.

Question 103

What is the dual nature of tau pathology in neurons?

Answer 103

Loss of function (less microtubule binding), Gain of function (aggregation, propagation, toxicity).

Question 104

What are promising therapeutic strategies to counteract tau spread?

Answer 104

Prevent seeding, Block tau release, Enhance clearance, Stabilise tau conformation.

Question 105

What is a novel idea for tau therapy discussed in the lecture?

Answer 105

Introduce a benign conformer that binds toxic tau and promotes non-toxic clearance or stabilisation.

Question 106

What is the risk of using alternative tau conformers as therapy?

Answer 106

They may still disrupt tau’s physiological roles, e.g. stabilising microtubules.

Question 107

Why is it beneficial to block tau release from neurons?

Answer 107

It could contain pathology to initial regions and prevent anatomical spread.

Question 108

What were the two types of tau spread experiments mentioned?

Answer 108

Microfluidic cultures (neurone-to-neurone spread), Rodent brain injections (spread through anatomical circuits).

Question 109

What is the significance of observing tau spread in both cell cultures and in vivo?

Answer 109

Confirms that tau can spread both via synapses directly and via complex anatomical networks in organisms.

Question 110

What is an exosome in the context of tau pathology?

Answer 110

A vesicle that can package and export misfolded tau to neighbouring cells.

Question 111

What are HSPGs and why are they important in tau uptake?

Answer 111

Heparan sulfate proteoglycans on the cell surface that facilitate endocytosis of misfolded tau.

Question 112

How can researchers confirm a specific tau uptake route?

Answer 112

By blocking or enzymatically degrading that route and observing reduced internalisation.

Question 113

What are possible ways to therapeutically block tau entry into neurons?

Answer 113

Develop inhibitors that block tau-receptor interaction (e.g. HSPG analogues), Or use antibodies that neutralise extracellular tau.

Question 114

Why is targeting tau entry complex?

Answer 114

The same mechanisms (e.g. HSPGs) have normal physiological roles and can’t be broadly inhibited without consequences.

Question 115

What is the difference between targeting tau phosphorylation vs. tau propagation?

Answer 115

Phosphorylation inhibitors act upstream (preventing misfolding), Propagation blockers act downstream (stopping spread of toxic forms).

Question 116

What is one drawback of anti-aggregation therapies?

Answer 116

Some drugs may break filaments into toxic oligomers, worsening symptoms.