Neurochemistry of Alzheimer’s disease

Alzheimer’s disease (AD) affects over 500,000 people in the UK and the annual cost of care is estimated at £11 billion. The disease is characterised by regionally selective gross cerebral atrophy, senile plaques, neurofibrillary tangles together with selective neurone and synapse loss. The principal neuronal types affected used glutamate or acetylcholine as transmitter. These changes produce a characteristic clinical syndrome of progressive cognitive dysfunction and behavioural abnormalities with declining activities of daily living. Current treatments are based reducing the breakdown of acetylcholine in the synaptic cleft and they provide symptomatic benefit for a majority of patients.

The research of this group focuses on the relationship between neurochemical changes in the brains of patients with AD and their particular symptoms. Thus we have shown that, in addition to the well-known relationship between acetylcholine and cognitive decline , there is a relationship between this system and non-cognitive, behavioural changes seen in patients with AD. This then provides a scientific rationale for the clinical improvement in this domain following treatment with acetylcholinesterase inhibitors (AChEI).

We are also interested in the mechanism of action of AChEIs and a newly approved drug in the AD field, memantine (Ebixa, Lundbeck). We have argued that AChEIs work by increasing the release of glutamate  that is reduced in AD as a consequence of glutamatergic cell and synapse loss . Memantine appears to have a glutamatergic mechanism of action, but one that is possibly at odds with our working hypothesis. We are keen to resolve this possible conflict.

Another area of great interest is second messenger/signalling systems that may be altered as a consequence of disturbed neurotransmission or as a primary pathological event. In collaboration with Dr Robert Williams we are investigating the status of signalling pathways involved in cell death and cell survival and using model systems to test whether any changes are a cause or consequence of AD neurochemical pathology.

Neurochemistry of Alzheimer's and other dementias