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An studying Alzheimer’s with Texas research lab

Wenfeng An
Wenfeng An

Alzheimer's disease is the most common cause of dementia, a general term referred to an impaired ability to remember, think or reason in daily lives. It is estimated that more than 6 million Americans may have dementia caused by Alzheimer's disease, mostly in people age 65 and older.

By Wenfeng An, professor & Markl Faculty Scholar in Cancer Research, Department of Pharmaceutical Sciences

Alzheimer’s is named after Alois Alzheimer, a German psychiatrist and neuropathologist, who, in 1906, first reported abnormal changes in the brain of a patient who suffered from dementia, including abnormal protein plaques and tangles. The latter remain the defining neuropathological characteristics of the disease today. However, their molecular composition was not revealed until the mid-1980s as being amyloid-b plaques and tau tangles, respectively.

Since then much has been learned about their roles in the pathological process of Alzheimer's disease. It is clear that age is a major risk factor of Alzheimer’s. The number of plaques and tangles increases in their brains as people get older. The earliest clinical phase of Alzheimer's disease is called amnestic mild cognitive impairment (aMCI), where an individual starts to forget important appointments or recall recent events.

According to Wei Cao, a professor of anesthesiology at the University of Texas Health Science Center at Houston, McGovern Medical School, “in addition to having β-amyloid plaques and tau protein tangles, the brains of patients with Alzheimer’s disease have a marked inflammatory response, which might be more of a problem than plaques themselves.”

However, the molecular triggers for neuroinflammatory response and factors mediating and regulating the process remains enigmatic.

In the recently funded NIH R01 project, Cao teamed up with An in investigating how antiviral immune response is coupled to derepressed transposon activity during Alzheimer's disease pathogenesis. Antiviral defense mechanisms control nucleic acid-based parasites, most noticeably the invading viruses.

Type I IFN (IFN) cytokines, a key component of antiviral innate immunity, is a product of signaling activation of mammalian nucleic acid innate immune sensors that detect viral genomes or their replication products.

Cao’s lab recently reported that plaque-associated microglia innately reacted to nucleic acid-containing amyloid β plaques and promote chronic gliosis and synapse loss in various Aβ models. Her lab has since confirmed a prominent IFN pathway activation in different murine tauopathy models.

Senescent cells dysregulate their epigenome and derepress transposable elements (including L1 retrotransposons), which are widely distributed in the genome. Consequently, L1 triggers an antiviral innate immune response, resulting in IFN production.

In parallel, her lab found that tau overexpression relaxed neuronal heterochromatin, which is correlated with elevated transcription of L1 and other TEs in tauopathy brains. In this collaborative project, An’s lab provides scientific and technical expertise in studying L1 jumping genes and will be instrumental in analyzing the role of L1 derepression in neuroinflammation using animal and cell-based models.