Alzheimer's Disease: Brain Patholoy of Tauopathies

Brains of patients with extensively developed pathology of the cytoskeletal protein tau show massive shrinkage due to loss of neuronal mass, including not only cells, but most importantly their connecting processes (left panel).
The affected cells and processes are filled with biochemically abnormally modified aggregates of tau proteins (tangles, middle panel), which may not be very toxic themselves, but probably are more a way to store a toxic precursor, and therefore correlate still rather well with brain atrophy and clinical dementia. Recent evidence indicates that this abnormality develops much earlier in the disease process than previously thought, already before any impairment is evident. It is thus among the very first biochemical abnormalities of the respective illnesses.
As viewed with the electron microscope, tangles are composed of aggregates with a certain regularity of structure, the P aired Helical Filament (PHF, right panel). All tau proteins in this structure are biochemically abnormal.

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Cellular Pathology of Neurofibrillary Degeneration

On the level of an individual brain cell, the pathology develops gradually through several stages over an extended period of time (Illustration reproduced from Braak, Braak & Mandelkow (1994) Acta Neuropathol. 87: 554-567).
Biochemically abnormal tau proteins can already be seen prior to formation of overt aggregates (pretangles, left panel). Nerve cells and their arbor of processes are still well maintained, with occasional microstructural abnormalities on selected processes (dendritic spines). It is conceivable that the pathology may be reversible at this stage.
Further along tangles appear in selected parts of the cell. Processes are grossly atrophied and truncated (middle panel). The nerve cell may no longer be available to contribute to cognitive processing.
In the severe stage of cell pathology, the nerve cell is filled with tangles and has no longer any processes, but is still alive (right panel). Eventually it will die and the tangle is shed into the extracellular space, where it may be degraded or obscured by coaggregation with other proteins (e.g. in certain types of amyloid plaques, the other major feature of protein abnormality in Alzheimer's disease

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Molecular Pathology of Tau Protein          

On the molecular level tau is understood to perform a specialized function in the regulation of the microtubules, a very central dynamic component of the nerve cytoskeleton. This function is tuned by introducing (kinases) or removing (phosphatases) phosphate groups into the protein at various locations (top panel).
The transition into an abnormal form is caused by an excess of phosphates (hyper-phosphorylation), imparting an abnormal folding on the protein (middle panel).
In this form tau is no longer able to interact with microtubules, affecting their integrity adversely (bottom panel). Rather it interacts with itself, giving rise to Paired Helical Filament aggregates, and later mature tangles. Altered dynamics of the microtubule network is thought to impair transport processes, which are vital to the sustenance of the nerve cell connections. Failure of this function leads to atrophy of the respective nerve cell processes and electrical isolation of the nerve cell