Maria Burke
‘We saw wonderful effects in terms of reducing neurodegeneration and neuroinflammatory responses, and even rescuing behaviour deficits.’
US researchers have shown that a novel peptide can reverse the loss of nerve cells in mice with Alzheimer’s disease. It appears to interfere with an overactive enzyme involved in neurodegenerative diseases and could offer a pathway for new treatments.
The enzyme CDK5 is a cyclin-dependent kinase involved in the development of the central nervous system and transmitting nerve impulses. When it binds to a small protein called P35, it undergoes structural changes that allow it to phosphorylate (add a phosphate molecule to) its targets.
However, in neurodegenerative diseases, P35 is split into a longer-lasting protein called P25. When P25 binds to CDK5, the enzyme becomes more active and phosphorylates other molecules as well as its usual targets, including the Tau protein. Hyperphosphorylated Tau proteins form the tangles that are one of the characteristic features of Alzheimer’s disease.
The above video explains the link between Tau proteins and Alzheimer's. Video credit: Alzheimer's Research UK.
P25 has been linked to several diseases, including Alzheimer’s, Parkinson’s and frontotemporal dementia, and has become a target for small-molecule drugs in development. However, due to side-effects, none have reached clinical trials.
Now a team from the Massachusetts Institute of Technology has designed a peptide to target P25 with promising results in tests on cultured nerve cells (neurons) and in mice models. The peptide contains a sequence identical to that of a segment of CDK5, which is critical for binding CDK5 to P25.
‘From a peptide drug point of view, usually smaller is better,’ says senior author Li-Huei Tsai. ‘Our peptide is almost within that ideal molecular size.’
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When injected into mice with Alzheimer’s and hyperactive CDK5, the peptide reduced DNA damage, neural inflammation, and neuron loss. Tests with another mouse model of Alzheimer’s with a mutant form of the Tau protein showed reductions in both Tau pathologies and neuron loss.
The team also reports that mice treated with the peptide were much better at learning to navigate a water maze than the control group. Significantly, the team found that the peptide did not interfere with CDK1 – an essential enzyme that is structurally similar to CDK5 – which might help to limit side-effects.
Li-Huei Tsai is a world-leading researcher into neurodegenerative disease.
‘We found that the effect of this peptide is remarkable,’ says Tsai. ‘We saw wonderful effects in terms of reducing neurodegeneration and neuroinflammatory responses, and even rescuing behaviour deficits.’
‘This study unlocks one of the most promising targets against dementia by finding a way around the problem of non-specific effects of small molecule drugs (previously attempted),’ says Edward Avezov of the UK Dementia Research Institute at the University of Cambridge.
‘The compelling data on the neuroprotective effect of their designed inhibitory peptide, capable of penetrating neurons, confirms that targeting the Cdk5 pathway is beneficial, that a peptide-based approach is valid and opens the doors to the development a much sought-after treatment for potentially multiple neurodegenerative diseases.’
However, he adds that translating this breakthrough to human treatment, if proven feasible, will most likely take many years, and will require several hurdles to be overcome.
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