Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export
Abstract
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.
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Tau-mediated neurodegeneration arises from multiple pathological mechanisms including loss of normal function, gain of toxic function, aggregation, and mislocalization.
“Tau-mediated neurodegeneration arises from multiple pathological mechanisms, including loss of normal function [37–42], gain of toxic function [43–46], aggregation [44, 47–49], and mislocalization [50–52].”
From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [40]
Additional physiological functions for tau include regulation of iron export and insulin signaling.
“Additional physiological functions for tau include regulation of iron export and insulin signaling [139, 140].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [139]
Tau deficiency impairs ferroportin iron export by retaining APP in the endoplasmic reticulum so that it can no longer be trafficked to the neuronal surface, where it can couple its ferroxidase activity to ferroportin.
“Tau deficiency impairs ferroportin iron export by retaining APP in the endoplasmic reticulum so that it can no longer be trafficked to the neuronal surface, where it can couple its ferroxidase activity to ferroportin.”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [85]
MAPT deficiency induces intracellular iron accumulation, which causes degeneration of dopaminergic neurons, leading to parkinsonism with dementia in mice.
“Microtubule-associated protein tau (MAPT) deficiency induces intracellular iron accumulation, which causes degeneration of dopaminergic neurons, leading to parkinsonism with dementia in mice.85”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [85]
In mice, genetic ablation of endogenous tau is well tolerated, with a minor motor phenotype developing only after 12-16 months.
“In mice, genetic ablation of endogenous tau is well tolerated with a minor motor phenotype developing only after 12–16 months (12–14).”
From Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy (2017) · cites this paper as [12]
Mice that completely lack tau have proven to be phenotypically normal in learning/memory and general cognition, with a minor motor phenotype developing later in life.
“Surprisingly, mice that completely lack tau have proven to be phenotypically normal in terms of learning/memory and general cognition (13, 14, 50) with a minor motor phenotype developing later in life, the severity of which varies (12–14, 56).”
From Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy (2017) · cites this paper as [12]
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“Moreover, the toxic tau may cause defect in axonal transport along microtubules (Wang and Mandelkow, 2016), during which iron export can be damaged, resulting in iron accumulation (Lei et al., 2012).”
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- Authors
- Lei, P., Ayton, S., Finkelstein, D. I., Spoerri, L., Ciccotosto, G. D., Wright, D. K., Wong, B. X. W., Adlard, P. A., Cherny, R. A., Lam, L. Q., Roberts, B. R., Volitakis, I., Egan, G. F., McLean, C. A., Cappai, R., Duce, J. A., & Bush, A. I.
- Affiliations
- Mental Health Research Institute (AU)
- The University of Melbourne (AU)
- Corresponding author
- Bush, Ashley I
- ORCID
- Venue
- Nature Medicine
- Published
- 2012-01-29
- Volume
- 18
- Issue
- 2
- Pages
- 291-295
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2039314393
- Cited by
- 594
- References
- 33
- Citations by year
- 2026: 28 · 2025: 25 · 2024: 50 · 2023: 47 · 2022: 49 · 2021: 54 · 2020: 36 · 2019: 47 · 2018: 38 · 2017: 45 · 2016: 38 · 2015: 37 · 2014: 39 · 2013: 39 · 2012: 21
- FWCI
- 29.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- tauopathy, Parkinson's disease, Alzheimer's disease, parkinsonism, amyloid precursor protein, ferroportin, iron export, clioquinol, iron chelation, substantia nigra, neurofibrillary tangles, MPTP mouse model, brain atrophy, cognitive impairment, soluble tau
- MeSH terms
- Age Factors, Aged, Animals, Brain, Brain Chemistry, Ceruloplasmin, Dementia, Humans, Iron, Male, Amyloid beta-Protein Precursor, tau Proteins, Mice, Knockout, Parkinsonian Disorders, Mice
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