Alzheimer’s disease is a neurodegenerative disease characterized by a progressive decline in mental functions and memory loss. Along with frontotemporal dementia and some other neurodegenerative disorders, Alzheimer’s disease has been associated with an accumulation inside neurons of abnormal clumps of a protein called “tau.”
The tau protein is important for brain health, stabilizing structures called microtubules inside neurons. In Alzheimer’s disease and other tauopathies (i.e., diseases linked with the abnormal accumulation of tau), tau proteins aggregate into toxic and insoluble clumps that are harmful to brain cells, gradually leading to their death.
Researchers at Zhejiang University, Xiamen University and other institutes in China recently carried out a study aimed at better understanding the processes via which tau aggregation contributes to the death of neurons in patients with Alzheimer’s disease. Their findings, published in Nature Neuroscience, suggest that these tau clumps prompt the reactivation of transposable DNA elements in neurons, which can in turn lead to their death.
“Once tau aggregates are formed, their neurotoxicity significantly contributes to neuronal death and cognitive decline in tauopathies, with Alzheimer’s disease being the most well-known example,” wrote Wei Liu, Song-Ang Wu and their colleagues in their paper. “Despite its central pathogenic role, however, effective therapeutic strategies targeting the neurotoxicity of tau remain poor. We demonstrate the pathogenic role of neuronal cell death in tau-related neurodegeneration (PS19 mouse model).”
How tau aggregates affect transposable DNA elements
The researchers carried out experiments involving mice that are genetically engineered to also exhibit abnormal tau aggregation in neurons, resembling the one associated with Alzheimer’s disease and other tauopathies. These mice, called PS19 mice, also typically behave in ways that indicate their memory and brain functions are progressively declining.
Liu, Wu and their colleagues tried to better understand how tau aggregates influence the organization of DNA inside their neurons. They specifically looked at whether the tau clumps disrupted heterochromatin, a tightly packed form of DNA that typically prevents harmful genetic code from being activated.
The team found that tau aggregates did in fact influence heterochromatin, leading to the activation of genes that are typically silent. These genes prompted the production of RNA molecules called Z-RNAs, which in turn activated a molecule that plays a role in inflammation and cell death, called Z-DNA-binding protein 1 (ZBP1).
“Tau-expressing neurons undergo cell death through Z-DNA-binding protein 1 (ZBP1) activation triggered by endogenous Z-RNAs,” wrote the authors. “These Z-RNAs are derived from reactivated transposable elements that are typically silenced within heterochromatin. Tau aggregates show a strong affinity for H3K9me3-modified chromatin, effectively sequestering these epigenetic marks from heterochromatin protein 1 (HP1), thereby disrupting the condensation of constitutive heterochromatin.”
A new possible route for preventing neuronal death
The recent paper by Liu, Wu and their collaborators pin-points a process via which the aggregation of tau could lead to neuronal death in tauopathies. In addition, it shows that blocking ZBP1 activity could be a possible therapeutic target for preventing or limiting tau aggregation-related cell death.
“Clinically, an inverse correlation between ZBP1 expression levels in excitatory neurons and cognitive performance in individuals with Alzheimer’s disease was observed,” wrote Liu, Wu and their colleagues. “Importantly, Zbp1 haploinsufficiency significantly ameliorated cognitive deficits in aged (24-month-old) tau-transgenic mice, highlighting the therapeutic potential of ZBP1 inhibition to combat neurodegeneration in tauopathies.”
Other researchers could soon set out to investigate the new mechanisms uncovered by the authors further. If they are validated in humans, the team’s findings could eventually guide the development of new treatments designed to limit cell death and the associated decline in mental functions in patients with Alzheimer’s disease or other tauopathies.