The
microtubule-associated protein tau has risk alleles for both
Alzheimer's disease and
Parkinson's disease and mutations that cause brain degenerative diseases termed
tauopathies. Aggregated tau forms neurofibrillary tangles in these pathologies, but little is certain about the function of tau or its mode of involvement in pathogenesis. Neuronal
iron accumulation has been observed pathologically in the cortex in
Alzheimer's disease, the substantia nigra (SN) in
Parkinson's disease and various brain regions in the
tauopathies. Here we report that tau-knockout mice develop age-dependent brain
atrophy,
iron accumulation and SN neuronal loss, with concomitant cognitive deficits and
parkinsonism. These changes are prevented by oral treatment with a moderate
iron chelator,
clioquinol.
Amyloid precursor
protein (APP)
ferroxidase activity couples with surface
ferroportin to export
iron, but its activity is inhibited in
Alzheimer's disease, thereby causing neuronal
iron accumulation. In primary neuronal culture, we found loss of tau also causes
iron retention, by decreasing surface trafficking of APP. Soluble tau levels fall in affected brain regions in
Alzheimer's disease and
tauopathies, and we found a similar decrease of soluble tau in the SN in both
Parkinson's disease and the
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP) mouse model. These data suggest that the loss of soluble tau could contribute to toxic neuronal
iron accumulation in
Alzheimer's disease,
Parkinson's disease and
tauopathies, and that it can be rescued pharmacologically.