According to a new study, a special protein disposal system, currently found only in neurons, is linked to central hallmarks of Alzheimer’s disease [1].
The membranal proteasome
Alzheimer’s disease is defined in part by two protein aggregates in the brain: amyloid-β plaques outside cells, and tangles of the protein tau inside neurons. In rare inherited tauopathies, the tau protein itself carries a mutation that makes it prone to clumping; however, in sporadic Alzheimer’s, which constitutes the vast majority of cases, tau has no mutation and is not overproduced [2]. What exactly nudges normal tau towards aggregation is not completely understood. A new study from Columbia University, published in Nature Neuroscience, tackles this question heads-on.
A cell has mechanisms to handle excess or misbehaving proteins. One such mechanism is the proteasome, a barrel-like protein complex that ingests such proteins and chops them up into small chunks (peptides). In most cells, proteasomes reside in the cytosol, but as the same team discovered a few years ago, neurons are different: they also have proteasomes that insert themselves into the cellular membrane, taking in proteins from the cytosol and spewing peptides from the other end into the intercellular space. The researchers called these “neuroproteasomes” and have been studying them ever since.
“Prior studies could not capture how tau misfolds in the first place in Alzheimer’s disease, but understanding how tau aggregation begins is critical if we want to create therapies that prevent neurodegeneration before it starts,” said the new study’s senior author, Kapil Ramachandran, assistant professor of neurological sciences.
Block the exits
In this new study, the team investigated the possible role of neuroproteasomes in tau aggregation. First, they had to devise a way to shut down these complexes without touching the cytosolic proteasomes. To do so, they developed compounds that can jam neuroproteasomes from the extracellular end but are too big to enter the cell.
The researchers then looked at what proteins become more prone to aggregation with neuroproteasomes shut down. Four proteins came up on top, including tau. This was confirmed in neurons from hTau-knock-in mice, a mouse model of endogenous human tau.
Interestingly, other inhibitors that work on all proteasomes – both cytosolic and membrane-bound – did not induce insoluble (aggregated) tau. This seems counterintuitive: why would tau be less prone to aggregation if all proteasomal machinery is blocked? Further experiments produced the following hypothesis: inhibiting the cytosolic proteasome triggers a compensatory cleanup response, which is based on autophagy and lysosomes that effectively clear the aggregates. However, the same compensatory mechanism doesn’t kick in when only neuroproteasomes are clogged. When both cleanup systems are shut down, aggregates reappear.
Morphological analysis confirmed that blocking neuroproteasomes produces tau filaments that looked exactly like those associated with Alzheimer’s. The insoluble tau in them had the same molecular weight and was phosphorylated at the same sites as in Alzheimer’s.
A genetic risk factor fits in
To connect this to genetic risk, the authors needed to know what the neuroproteasome interacts with at the membrane. The list of identified binding partners included ApoE, Alzheimer’s strongest genetic predictor. The ApoE4 isoform of this protein is strongly associated with Alzheimer’s, while ApoE2 is protective, and ApoE3, the most widespread type, is considered neutral.
Given that physical link, do the three ApoE isoforms regulate the neuroproteasome differently? In humanized ApoE knock-in mice, surface neuroproteasome levels were indeed strongly reduced in ApoE4 hippocampal tissue compared with the other two isoforms.
The same held in human postmortem brains: people who carry two copies (being homozygous) of this harmful allele were found to have significantly lower neuroproteasome levels than people who are homozygous for APOE3. Moreover, APOE3/3 brains from Alzheimer’s patients have lower neuroproteasome levels than APOE3/3 controls, showing the disease’s effect. These levels fell further in high-pathology regions, showing an inverse relationship between neuroproteasome abundance and tau burden.
Age is the strongest risk factor for Alzheimer’s. To test the relationship between aging and neuroproteasome levels, the researchers looked at wild-type mice and saw these levels decline beginning at around 12 months.
Using neurons from mice expressing human tau and ApoE, the researchers found that the amount of neuroproteasome inhibition needed to trigger aggregation depended sharply on genotype. ApoE4 neurons formed insoluble tau after losing only 20% of neuroproteasome activity; ApoE3 needed 60%, and ApoE2 needed 85%.
In the researchers’ proposed model, ApoE sets a neuron’s “proteostatic reserve.” ApoE4 neurons run close to the edge with less reserve, so an insult, such as aging, tips them into aggregation relatively easily. Conversely, ApoE2 neurons have double protection, both by higher baseline neuroproteasome levels and by greater tolerance to losing them, while ApoE3 sits in the middle, which resembles the correlation between these genotypes and Alzheimer’s.
In their previous paper, the authors suggested that the neuroproteasome may have certain signaling functions; however, this study still leaves many of its details unresolved, including its exact role and how it is affected by ApoE, so they plan to dig deeper. “The links between tau filament formation and ApoE variants and aging, Alzheimer’s greatest risk factors, suggest we may have found a mechanism to explain how an important aspect of the disease gets started,” Ramachandran said. “Our hope now is that our findings open a whole new area of research that eventually helps patients.”
Literature
[1] Paradise, V., Konrad-Vicario, K. D., Nguyen, C., Sharif, N. A., Wang, X., Mukim, R. D., … & Ramachandran, K. V. (2026). Neuroproteasomes regulate endogenous tau paired helical filament formation in an APOE genotype-and age-dependent manner. Nature Neuroscience, 1-13.
[2] Gendron, T. F., & Petrucelli, L. (2009). The role of tau in neurodegeneration. Molecular neurodegeneration, 4(1), 13.
[3] Ramachandran, K. V., & Margolis, S. S. (2017). A mammalian nervous-system-specific plasma membrane proteasome complex that modulates neuronal function. Nature structural & molecular biology, 24(4), 419-430.
View the article at lifespan.io
