Evidence for a novel neuronal mechanism driving Alzheimer’s disease, upstream of amyloid (Link to the paper)

An international team of clinicians and neuroscientists* today published a new perspective on the process of neurodegeneration. Their findings review evidence for a mechanism upstream of amyloid including the key neurochemical driving this process. The paper focuses on a selective group of neurons (‘the isodendritic core’). These cells have a different provenance from neurons in the rest of the brain and have previously been identified as primarily vulnerable in Alzheimer’s disease (AD). The authors acknowledge that amyloid is a significant factor in AD once it has progressed but note that it is not present in these neurons in the early stages. If damage occurs to these vulnerable neurons in adulthood, these neurons will respond by mobilising a retaliatory mechanism. This mechanism normally promotes growth of neurons in embryos and early life but in adulthood is detrimental.

The review describes how the pivotal molecule that drives this process, is a bioactive 14mer peptide, T14, that selectively activates a single target receptor. In the mature brain instead of restoring normal function, T14 leads to the death of neurons and initiates an adverse snowball effect that gains momentum over time.

The isodendritic core neurons, found deep in the brain, are responsible for arousal and sleep/wake cycles and are not directly related to higher functions such as memory. Hence, the process of degeneration can continue without obvious symptoms until the damage spreads to areas that underlie cognition. The explanation offered in this article may account for the long-time lag of 10-20 years from onset of neuronal loss to appearance of cognitive impairment.

The review reports how T14 can be detected at a very early stage of AD and therefore could be a pre-symptomatic indication that neurodegeneration had started and as such could be developed as a biomarker. Moreover, the authors describe how a cyclated version, NBP14, can act as a blocker of T14.  NBP14 has been shown to prevent memory dysfunction in a mouse model of AD and its mechanism of action has been demonstrated in a variety of studies including in post mortem human brain tissue. As such NBP14  could eventually inspire a new therapeutic strategy.

* Dr Sara Garcia-Ratés, Neuro-Bio Ltd, Dr Maria Salud Garcia-Ayllon (Fundación FISABIO, Spain), Dr Neus Falgás (Hospital Clinic Barcelona, Spain), Dr Sharon Brangman (Upstate Center of Excellence for Alzheimer’s Disease, SUNY, US), Prof Margaret Esiri (Oxford University hospitals, UK), Prof Clive Coen (King’s College London, UK), Prof Susan Greenfield, Neuro-Bio Ltd. )

Quotes from authors external to Neuro-Bio 

Dr Maria Salud García-Ayllón, researcher at Fundación FISABIO says: This is a novel mechanism that offers a new promising therapeutic strategy that should be explored further

Dr Sharon Brangman, Chair of Dept Geriatrics SUNY Upstate Medical University says: As a clinician it is very exciting to see how this work focuses on mechanisms that are upstream of amyloid with very compelling implications for the development of AD. The clinical implications are significant

Dr Neus Falgás, neurologist at Hospital Clinic de Barcelona, says: This approach proposes a potential mechanism considering the selective vulnerability of neuromodulatory subcortical systems in Alzheimer’s Disease.

 Prof Margaret Esiri, Emeritus professor at Oxford University, says: This review brings together important findings that are relevant to a novel approach to preventing or curtailing Alzheimer’s disease.

 Prof Clive Coen, Emeritus professor at King’s College London, says: Greenfield’s multidisciplinary research, which has been consistently innovative for 50 years, has identified a novel neurobiological system, one that seems to be intimately involved in neurodegenerative processes.