Understanding Alzheimer’s Disease

A growing global challenge

Global impact

150 MILLION

People affected by 2050¹

ECONOMIC BURDEN

$14 TRILLION

Projected cost by 2050²

TREATMENT WINDOW

10-20%

Annual MCI progression rate³

Current Treatment Landscape

Existing Medications

Available drugs treat symptoms only

Major side-effects of approved drugs

Frequently difficult to access and administer

Treatment Challenges

No standardized measurements for risk

Underlying disease mechanism still unclear

Multifactorial approach necessary for treatment

In Alzheimer’s Disease there is a reduction in the levels of a growth factor, BDNF, and increasing this has been suggested as a potential treatment option⁴. Supporting this, increasing BDNF in animal models of Alzheimer’s Disease has many positive neuroplasticity effects including preventing neuronal death, activating neuronal function, building new synapses, and improving both learning and memory⁵. Despite this potential, directly administering BDNF is not feasible in humans⁶.

In Alzheimer’s Disease we see the following:

BDNF levels in brain

Neurogenesis (nerve growth) over time

Synaptogenesis (nerve connections) over time

Neural functioning over long-term

The Science of BDNF / TrkB Receptors

Understanding the key to neuroplasticity

What is BDNF?

Brain-derived neurotrophic factor (BDNF), first described in 1982⁷, is one of the most widely distributed and extensively studied nerve growth stimulators (neurotrophins) in the mammalian brain⁸. It is involved in neuronal development, neuroprotection, and modulation of synaptic interactions - critical for both cognition and memory⁹. Increasing BDNF levels has long been recognized for its ability to elicit a rapid increase in multiple neuroplasticity changes which are positive to neuronal and brain health¹⁰.

In terms of Alzheimer’s Disease, there is a long-recognized reduction in BDNF levels¹¹,and for this reason an increase in brain BDNF levels has been suggested as a treatment option for Alzheimer’s Disease and Mild Cognitive Impairment¹². Supporting these suggestions, BDNF in animal models of Alzheimer’s Disease prevents neuronal death, activates neuronal function, builds new synapses, and improves both learning and memory¹³ ¹⁴. Despite this potential, administering BDNF clinically has not been feasible in humans, despite multiple efforts¹⁵. However, stimulation of certain receptors, such as the serotonin 5-HT2A receptor, can increase BDNF levels¹⁶.

Neuroplasticity

The ability of the CNS to adapt in a positive manner, including new nerve growth (neurogenesis)

Synaptogenesis

The increase in connections between the nerves via an increase in the number of synapses

Neuroprotection

This includes increased neuronal resilience and a reduction in neuroinflammation

The TrkB Receptors

BDNF binds to a pair of TrkB receptors (Tropomyosin-related kinase receptors, type B)¹⁷. This binding stimulates a large number of activities within the neuron, occurring via so-called second-messengers systems, and it is these second messenger systems which lead to all of the neuroplasticity effects of BDNF¹⁸. While the TrkB system can be activated indirectly by receptors, such as the serotonin 5-HT2A receptors¹⁹, it is also possible that it can be stimulated directly to help overcome Alzheimer’s disease²⁰. It is possible that drugs which can enhance BDNF / TrkB activation by more than one mechanism, such as via 5-HT2A receptor activation and by direct actions on TrkB receptors, may be more likely to be effective clinically. Excitingly, the data available suggests that ZYL-314 may be able to do this.

Structure

TrkB receptors span the neural membrane connecting the outside of the cell with second-messenger systems within the neuron. A pair of receptors twist closely together (called a receptor dimer), and both of these are needed to allow binding to BDNF. Once BDNF binds it triggers a series of actions.

Activation

The TrkB dimers bind with high specificity to BDNF which triggers a rapid activation of several different second-messenger systems within the cell. These increase both the short-term release of BDNF, and via increased gene expression, also increase long-term release of BDNF to increase neuronal growth.

Function

Levels of CREB (cAMP response element-binding protein) are reduced in Alzheimer’s disease. However, BDNF / TrkB activation leads to an increase in CREB, which directly regulates DNA and gene expression critical to neural plasticity, long-term memory formation, and spatial memory.