Tip60: A realistic target to treat Alzheimer’s disease?

• Alzheimer’s disease (AD) is the most common brain disease affecting older people.
• Dr Felice Elefant, a professor at Drexel University in Philadelphia, USA, and her PhD student Akanksha Bhatnagar uncovered that the levels of an enzyme called Tip60 are depleted in the brain of Alzheimer’s patients, negatively affecting production of diverse protein variants.
• Their research shows that increasing Tip60 has a beneficiary effect by restoring neuronal protein diversity needed for learning and memory.
  
• As a potential therapeutic approach, the team will test small molecules designed to enhance Tip60’s enzyme activity.

Alzheimer’s disease (AD) is an incurable disease that affects cognitive function. The greatest risk factor for developing AD is ageing – most people with Alzheimer’s are over 65 years old. AD is a progressive condition that affects parts of the brain that control thought, memory, and language. The main features of Alzheimer’s pathology include the loss of connections between neurons and protein aggregates called amyloid plaques, which are found in the patient’s brain.

Over the years, extensive research on AD has increased our understanding of the pathology of this devastating condition, although insights on the cause of the disease and treatment options lag behind. One important finding is that the protein-making machinery goes awry in AD. Examining this further, a team of researchers at Drexel University and the University of Pennsylvania, USA, uncovered the role of an enzyme called Tip60. Tip60 normally plays a significant role in producing the right kind of proteins for a healthy brain, but it malfunctions in the brain of Alzheimer’s patients.

Protein production goes wrong in Alzheimer’s

Professor Felice Elefant and her PhD student, Akanksha Bhatnagar, at Drexel University in the USA revealed that the levels of the enzyme Tip60 are depleted in Alzheimer’s patients’ brains, which may contribute towards the disease and its progression.

Tip60 has been shown to have a histone acetyltransferase (HAT) activity, meaning that it binds to DNA-wrapping proteins to turn genes on and activate protein production. However, the team uncovered for the first time an unprecedented dual role for Tip60: it also binds certain RNAs in the brain to regulate which types of proteins arise from them.

The levels of enzyme Tip60 are depleted in Alzheimer’s patients’ brains, which may contribute towards the disease and its progression.

DNA contains genes which encode the sequence of all proteins produced in our body. Gene activation is a process tightly regulated within cells to ensure that the right genes are switched on in the correct cell types and stages. This process is particularly important in the brain, given that it contains more than 3,000 different cell types. RNA, which is derived from DNA, is ultimately converted into proteins through a process called translation. The mechanisms that control which genes are activated and when, and which RNA variants will generate proteins, are described with the general term ‘epigenetics’.

Alternative RNA splicing, for example, allows for more than one protein to be derived from a single gene. This is the critical process whereby specific protein variants are produced from RNA to create the protein diversity within a cell necessary to support its functional needs. Brain cells are continuously responding to environmental stimuli and rewiring to allow new memories to be created. These specialised neurons especially rely on RNA splicing to support their complex functions and to generate the protein variants needed for neuroplasticity (structural changes or adaptions in the brain in response to stimuli), which is required for learning and memory processes.

Elefant’s lab had previously shown that the classical HAT property of Tip60 is negatively affected in the brains of AD patients, leading to certain neuronal genes getting inactivated. Using a fly experimental AD model that displays classic features of human AD pathology, they demonstrated that increasing Tip60 reduces neuronal death, restores memory, and promotes neuronal functions.

Tip60 malfunction alters protein diversity in the AD brain

Taking their discoveries further, the team demonstrated in their most recent publication in the renowned Journal of Neuroscience that Tip60 is not only binding DNA-wrapping proteins to activate gene expression in the brains of AD patients. It is also involved in the regulation of RNA alternative splicing (Figure 1). These findings suggest that the altered levels of Tip60 on AD brains affect not only gene activation but also the generation of diverse protein variants.

Using the same fly experimental AD model, Elefant and Bhatnagar show that malfunction of Tip60 is a key cause of AD, as the malfunctioning Tip60 fails to make essential proteins for neuronal function and for cognition. The team also showed that Tip60 has a similar function in the human brain (Figure 2). Indeed, by analysing human samples the researchers observed that Tip60-RNA targeting is also disrupted in the brain of people suffering from Alzheimer’s – particularly in the hippocampus, which is the region that controls memory and is mostly affected during the course of the disease.

Tip60 with its newly discovered role in regulating diverse protein variants may prove a realistic target to treat Alzheimer’s disease.

What’s even more interesting is that when Tip60 levels are brought back to normal, the disease pathology is relieved, suggesting that increasing Tip60 levels can be a potential therapeutic approach for Alzheimer’s. The researchers state: ‘We speculate that such Tip60-RNA binding disruptions ultimately contribute significantly to AD pathologies but can be protected against by increased Tip60 levels.’

Tip60 as a therapeutic target for AD

The next step for Elefant and her team is exploring the potential of Tip60 as a therapeutic target in AD. One way would be to directly enhance Tip60 activity in AD brain which would provide specificity of treatment. The team wants to focus on the HAT activity of Tip60 in gene activation. This would be a powerful selective approach because the AD brain displays reduced Tip60 histone acetylation leading to inactivation of critical synaptic plasticity genes and causing cognitive deficits. To achieve this, the team needs to further discriminate between the two functions of the enzyme and enhance its histone acetyltransferase activity (Figure 3).

With a computational drug design approach, Elefant and her colleagues designed and synthesised a novel set of small molecule compounds that can selectively activate Tip60 and promote its histone acetyltransferase activity. These novel compounds will be tested for therapeutic effectiveness in an Alzheimer’s disease model. Tip60 with its newly discovered roles in mediating gene activation and RNA/protein diversity in the brain may prove a realistic target to treat Alzheimer’s disease.