Alzheimer's Disease Biology

Question 1

Suggest how abnormal tau could cause neuronal dysfunction

Answer 1

Tau protein is primarily associated with microtubules, providing structural stability and facilitating axonal transport. Is abnormal when hyper-phosphorylated causing neuronal dysfunction by disruption of cytoskeleton (MT) integrity leading to axonal transport and synaptic dysfunction

Loss of Normal Function

• Tau normally stabilises microtubules, which are critical components of the neuronal cytoskeleton, supporting cell structure and facilitating intracellular transport along axons.
• When tau becomes hyperphosphorylated, its affinity for microtubules decreases, leading to microtubule destabilisation
• As a result, axonal transport is compromised
• Essential nutrients, organelles and neurotransporter vesicles are not delivered efficiently to synaptic terminals, impairing neuronal function

(Mudher et al., 2004)

Gain of Toxic Function

• Hyperphosphorylated tau tends to aggregate into paired helical filaments, eventually forming neurofibrillary tangles (NFTs). Before NFTs are formed, smaller oligomeric tau species can disrupt cellular function.
• These smaller aggregates are diffusible and toxic to cells. The oligomers can interfere with various cellular processes such as signalling pathways, synpatic function and possibly induce oxidative stress leading to cell death.
• The toxic gain of function by these tau species may contribute to synaptic dysfunction and ultimately neuronal loss (Chee et al., 2005).
• The molecular details of these disruptions were evidenced through experimental models where the introduction of mutant or phospho-mimicking tau leads to synaptic defects and behavioural abnormalities, indicating that the mere presence of such tau proteins is sufficient to initiate neurodegenerative processes (Mudher et al., 2004)
• Smaller oligomeric tau causes neurodegeneration by oxidative stress, apoptosis, necrosis or simple space occupying lesion

Counter

1. Reduce tau phosphorylation; kinase inhibitors
2. Microtubule stabilising agents (Quraishe et al 2017)

Question 2

Understand how tau causes degeneration and pathology spread

Answer 2

Misfolded tau seeds (likely oligomers) can propagate pathology across anatomically linked regions and cause neurodegeneration in prion-liked manner

Mechanisms of Tau-Induced Neurodegeneration

1. Toxic Gain of Function: When hyperphosphorylated, tau not only loses ability to stabilise microtubules but also gains toxic functions. The mechanism proposed include the induction of oxidative stress, activation of apoptotic pathways, disruption of cellular organelles, and potentially acting as a space-occupying lesion within neurons (Mudher et al., 2017).
2. Impact on Synaptic Function: Abnormal tau can disrupt synaptic function directly by mislocalising to dendritic spines and interfering with synaptic transmission. This disruption leads to synaptic loss, which is a major contributor to cognitive decline observed in tauopathies (Mudher et al., 2004).

Spread of Pathology

1. Cell-to-Cell Propagation: Recent evidence suggests that tau pathology can spready through neural networks in a prion-like manner. This concept has been supported by experiments showing that pathological tau, once formed, can induce misfolding of normal tau in neighbouring cells suggesting aggregates can be transmitted from one neuron to another from in vivo demonstration (Clavaguera et al., 2009).
2. Trans-synaptic Transmission: The transmission of tau pathology is thought to occur trans-synoptically, following the anatomical connections between brain regions. This transmission leads to a stereotypical pattern of spread, as postulated by Braak and Braak staging (traditional view). Pathological tau is thought to spread across synaptically connected neurons, contributing to the characteristic progression of clinical symptoms in disorders like Alzheimer’s disease (Braak and Braak, 1995; Clavaguera et al., 2014).
3. Tau Strains and Conformations: There is also evidence suggesting that different strains of misfolded tau can propagate distinct pathological patterns, similar to prions. These strains might underlie the diversity of tauopathies, including Alzheimer’s disease, progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), by propagating specific conformations of misfolded tau (Saunders et al., 2014)

Question 3

Based on the above identify suitable therapeutic interventions to counteract this

Answer 3

Tau-centric therapies can counter 1 (with kinase inhibitors, MT stabilising drugs) and 2 (anti-tau oligomer antibodies; preventing spread, anti-oxidants)

1. Reducing Tau Phosphorylation: Kinase inhibitors to stabilise microtubule network and normal axonal transport
2. Microtubule-Stabilising Agents: Such as NAP rescues tau-induced MT destabilisation and the associated phenotypes, such as synaptic defects and behavioural abnormalities. (Quraishe et al., 2013)
3. Tau Aggregation inhibitors: aims to prevent the formation of toxic oligomers and larger aggregates protecting neurons from tau accumulation
4. Immunotherapy: Anti-tau antibodies aim for immune system to recognise and eliminate pathological tau species before they can exert toxic effects or propagate to other neurons
5. Antioxidants: oxidative stress is one of the proposed mechanisms by which tau induces cellular damage, antioxidants could mitigate this stress and protect neurons from tau-mediated toxicity.
6. Tau mRNA Silencing: RNA-based therapies such as antisense oligonucleotides (ASOs) could reduce the overall production of tau protein. By lowering the levels of tau, the likelihood of abnormal tau formation and subsequent pathological events would be reduced.