Current strategies for the treatment of Alzheimer's disease and other tauopathies

The pathological hallmarks of Alzheimer's disease (AD) include abnormal intra- and extraneuronal tau and amyloid accumulation, respectively, accompanied by gliosis, oxidative stress and neuron loss. The discovery of mutations within the tau gene itself that cause clinical dementia (i.e., fronto-temporal dementia with Parkinsonism linked to chromosome 17 [FrDP17]) demonstrated that disruption of normal tau function independent of amyloidogenesis was sufficient to cause neuronal loss and clinical dementia. These studies demonstrate the need for therapeutics that either decrease the total pool of tau or selectively reduce aberrant forms of tau (i.e., hyperphosphorylated, misfolded etc.). To this point, therapeutic development for tauopathies, including AD, have primarily focused on either the phosphorylation of tau, as it is a downstream target for many kinases and signalling cascades, or inhibition of tau aggregation. Recent developments, however, suggest that pharmacological targeting of other mechanisms may hold therapeutic promise for the treatment of tauopathies.