Alzheimer's Disease and Frontotemporal Dementia

Tau

Several neurodegenerative diseases are characterized by the presence of abnormal intracellular protein aggregates (clumps) of the protein tau. The most common of which is Alzheimer's disease where tau is changed by the addiction of phosphate molecules to make it hyperphosphorylated. This change is thought to stop it functioning normally and cause it to clump together with itself. As it clumps together, the folded shape of the protein changes into a form that is extremely difficult to change back. These mis-folded tau proteins link themselves into long chains which pair up with another chain by wrapping around each other in a spiral. These complex structures are called filaments. These filamentous aggregates are associated with the death of neurons such as those that control memory, language and behaviour.

In Alzheimer's disease a second form of filamentous protein aggregate made of β-amyloid protein forms, and the presence of both tau and β-amyloid are defining neuropathological characteristics of Alzheimer's. Diseases with tau aggregates but without β-amyloid aggregates are called tauopathies. The most common tauopathy is Frontotemporal dementia with Parkinsonism linked to chromosome 17, which is a mouth full that is abbreviated down to FTDP-17.

The reason why tau mis-folds and aggregates isn't known, but some families have a history of tauopathy and analysis of their DNA shows mutations in the tau gene MAPT. More than 55 mutations in MAPT have been described in people with FTDP-17, leading to clinical phenotypes and tau pathology similar to those of tauopathies without mutations, such as Progressive Supra Nuclear Palsy (PSP), Cortical Basal Degeneration (CBD), Pick's disease (PiD) and Alzhimer's disease. However these represent 1% of all cases of tauopathies, the remaining 99% have no identified mutation and the cause remains unknown.

Inflammation is a central pillar of neurodegeneration and is seen at very early stages of tauopathy. Research in the Spillantini lab is currently aimed at understanding how aberrant inflammatory immune reactions to the developing tauopathy could exacerbate or even cause the disease.

Cell death

The death of a neuron is an irreversible stage in neurodegeneration. Whether the diagnosis is Parkinson's or Alzheimer's disease, eventually specific populations of neurons die. This is causes irreversible damage to the brain because unlike other organs like the liver or skin, neurons are not replaced by neighboring cells.

Cells die in a number of ways, usually the process is highly ordered and the result of a fate decision by the cell. The best described route of cell death is apoptosis in which the DNA is compacted down, the cell machinery is broken up, and the cell splits into numerous packages ready to be cleared away like bin bags. Sometimes the cell dies in a highly disordered fashion, bursting open in a process called necrosis. This form of cells death is thought to be a cause of inflammation, which may lead to more damage and necrosis. There are numerous routes of cell death each with their own characteristic mechanism and consequence.

Which route of cell death occurs in neurodegeneration is still unclear. Yet it is the ultimate consequence of all the various pathologies like tau or α-synuclein or β-amyloid. The Spillantini lab is actively researching the mechanism of cell death in neurodegeneration to identify inhibitors that could be used in therapies.

Inflammation

Microglia are the resident immune cells of the brain. Whether microglia are beneficial or detrimental to the health of neurons in neurodegeneration is unclear. A great body of evidence supports the case that inflammation is harmful to neurons and that this inflammation is due to the protein aggregates and degenerative processes of disease. On the other hand, it is clear that microglia are also capable of actively eating aggregate material leading to its clearance in a non-inflammatory manner. For example, loss of function mutations in the receptor TREM2 are a major risk factor for developing Alzheimer's, possibly due to a reduced ability to clear aggregates.

However, it has recently been seen that microglia recognise eat-me signals on live viable neurons suffering sub toxic stress leading to their engulfment and death through a mechanism coined: Phagoptosis. This engulfment is primarily driven by the detection of phosphatidylserine on the surface of cells which represents the phagocytic "eat-me" signal. We are currently investigating the presence of eat me signals on neurons with tau-protein aggregates seen in Alzheimer's and Frontotemporal dementia.