Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

A new study from the Department of Pharmacology sheds light on the link between the two major Alzheimer's disease pathologies.

It has been known for many years now that Alzheimer’s disease is triggered by the build-up of a small protein called amyloid-beta (Aβ), which is the major constituent of the pathological amyloid plaques that characterize the neuropathology of Alzheimer’s. The dominant hypothesis for how this trigger causes the disease itself, the amyloid cascade hypothesis, suggests that Aβ initiates a sequence of events that includes, critically, chemical alteration by excessive addition of phosphate groups (hyperphosphorylation) to the protein tau, itself a key component of Alzheimer’s neuropathology as neurofibrillary tangles. Only once this has happened, it is thought, will the full manifestations of the disease ensue. Exactly how Aβ might trigger the recruitment and hyperphosphorylation of tau has, however, remained unclear.


A new study from the Department of Pharmacology led by Dr. Alexander Jeans and Professor Nigel Emptage now sheds light on this process. Using slices from the rodent hippocampus, a brain region particularly vulnerable to Alzheimer’s pathology, the researchers found that application of the Aβ protein caused an increase in the amount of the neurotransmitter glutamate that neurons released, which in turn caused an abnormal enhancement of a physiological process called long-term depression (LTD) that regulates the strength of synaptic connections between neurons. LTD has previously been shown to require the tau protein, to which it normally causes the addition of phosphate groups at just two distinct sites.  Taylor et al. showed that either following exposure to Aβ, or following the induction of abnormally enhanced long-term depression alone, tau underwent an excessive hyperphosphorylation just as it does in Alzheimer’s disease.  Together, the data support a new mechanistic model linking Aβ to tau, wherein Aβ increases neurotransmitter release, enhancing synaptic long-term depression which in turn drives the pathological tau hyperphosphorylation necessary for the full expression of Alzheimer’s disease.

Not only does this study fill an important gap in our understanding of the molecular mechanisms of Alzheimer’s disease development, it also throws up interesting new potential therapeutic possibilities that might be exploited in the future. In particular, inhibition of the enzymes responsible for the excessive addition of phosphate groups to tau during enhanced long-term depression may be beneficial, as may inhibition of the particular type of synaptic glutamate receptors associated with the induction of long-term depression itself.

Read the full paper

Similar stories

New Research Highlights Importance of Early Years Development on Future Wellbeing

Oxford researchers involved nearly 4,000 children across the UK in three specially developed science lessons to educate pupils about brain development during early childhood. The SEEN (Secondary Education around Early Neurodevelopment) project was commissioned and funded by KindredSquared and is part of a wider drive to increase public understanding of how early experiences can shape the adults we become.

Evaluating risk to people with epilepsy during the COVID-19 pandemic - study wins international prize

In May 2020 our researchers initiated a global project to investigate how COVID-19 has affected people with epilepsy, their carers and health care workers.

Oxfordshire Young People Involved in Childline Research Project

New research conducted by the Neuroscience, Ethics and Society group and NeurOX Young People’s Advisory Group in the Department of Psychiatry at the University of Oxford, and the NSPCC, has looked at how Childline’s message boards help support young people.

New European initiative to accelerate the discovery and validation of biomarkers for neurodegenerative diseases

Members of the European Platform for Neurodegenerative Diseases (EPND) will establish a collaborative platform for efficient sample and data sharing, linking existing European research infrastructures to accelerate the discovery of biomarkers, new diagnostics and treatments for the benefit of people with neurodegenerative diseases such as Alzheimer's and Parkinson's.

PTSD in healthcare workers during pandemic could be exacerbated by past trauma

While some of the high rates of post-traumatic stress (PTSD) seen in healthcare workers during the pandemic are specifically COVID-19-related, a more significant number of cases were linked to trauma that occurred earlier in their lives, researchers at the University of Oxford have found.