Asceneuron targets the root cause of neurodegeneration in Alzheimer’s disease, one of the most critical healthcare challenges of this century

What is Alzheimer’s disease?

Alzheimer’s disease is a slowly progressing and irreversible disease causing the degeneration of nerve cells in parts of the brain which are important for cognition and memory. It the most common cause of dementia, a general term for loss of memory and other mental abilities severe enough to interfere with daily life. Dementia is estimated to currently affect more than 48 million people worldwide.

Age is the largest risk factor for Alzheimer’s disease and to date, no available treatments are able to slow down or stop the progression of the disease. Due to increasing life expectancy, Alzheimer’s disease is viewed as one of the largest healthcare problems of this century, imposing a major economic burden on societies in the Western and developing world.


What are the symptoms of Alzheimer’s disease?

Early symptoms of Alzheimer’s disease include short-term memory loss, as well as mood and behavior changes. As the disease progresses, Alzheimer’s patients gradually lose cognitive function (memory, language, orientation) and require assistance in performing daily activities. At an advanced stage, they need constant assistance due to more serious memory loss and difficulties with speaking, walking and swallowing.


Understanding Alzheimer’s disease

Alzheimer’s disease causes the degeneration of nerve cells in large parts of the brain. The main hallmarks of Alzheimer’s disease are:

  • Progressive accumulation of beta-amyloid (Aβ peptide in so called neuritic plaques) outside neurons, interfering with the neuron-to-neuron communication at synapses and possibly contributing to cell death.
  • Aβ peptides also accumulate as so-called vascular amyloid around the blood vessels of the brain, thereby interfering with the uptake of essential nutrients from the blood into the brain.
  • Abnormal deposits of the protein tau (neurofibrillary tangles) inside neurons, blocking the transport of cargo inside neurons. This is a major driver of neuronal dysfunction and cell death.

Eventually, both amyloid deposits and tangles cause irreversible damage in the brain, leading to atrophy of the brain and a loss of cognitive function.

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Comparison of a healthy brain (left) and a brain affected by Alzheimer’s (right):
Plaques and tangles lead to shrinkage of the brain and neuroinflammation


Asceneuron’s innovation in Alzheimer’s disease

Current Alzheimer’s treatment options can help extend the autonomy of Alzheimer’s patients and reduce their motor symptoms. However, none of them are able to slow down or stop the progression of the disease.

Based on the knowledge that the formation of neurofibrillary tangles drives the progression of Alzheimer’s disease, we have designed molecules which prevent the formation of these toxic tau aggregates in the brain. As such we are targeting the root cause of neurodegeneration. The underlying molecular mechanism is the inhibition of an enzyme that removes the sugar modification N-acetylglucosamine from tau and is termed O-GlcNAcase. As a result of O‑GlcNAcase inhibition, tau bears more of the sugar which blocks its aggregation into toxic assemblies.

With respect to symptomatic relief, the current drugs tend to work only for a restricted period of time and, based on their mode of action, can lead to side effects. The majority of Alzheimer’s drugs block the breakdown of the neurotransmitter acetylcholine, thereby compensating for the progressive loss of specific nerve cells which release acetylcholine. We are developing positive allosteric modulators of the M1 muscarinic acetylcholine receptor (M1 PAMs). M1 PAMs induce a change in the shape of the receptor enhancing binding to the neurotransmitter acetylcholine. As a result, receptor activity is potentiated so that it can still fulfill its signaling functions, critical for cognition, even in situations where acetylcholine levels are reduced as observed in Alzheimer’s and other dementias.


Patient associations

Alzheimer's disease key facts
ABOUT ALZHEIMER'S

60 to 80% of dementia cases


DEMENTIA WORLWIDE

2015      46.8 Million

2030      74.7 Million

2050     131.5 Million


GLOBAL COST OF DEMENTIA

2015          818 billion USD

2030     > 2000 billion USD


AGE OF PATIENTS

85+              37%

75<>84        44%     

65<>74        15%

<65                4%    

(US, 2016)