Central Role of Amyloid Oligomers in Alzheimer’s

In the aging brain, decreased clearance of amyloid monomers & their aggregation into toxic oligomers initiate Alzheimer’s pathology

Amyloid peptides are derived from the amyloid precursor protein, or APP, an integral membrane protein, in neurons and astrocytes in the brain. Through the enzymatic cleavage of APP, amyloid monomers are produced normally at low levels and cleared from the brain via cerebrospinal fluid. One view of Alzheimer’s disease is that APP is cleaved at an accelerated rate, producing increased amounts of soluble amyloid monomers. These monomers then aggregate to form larger soluble amyloid oligomers, that are neurotoxic and, over time, lead to loss of neuronal synapses, nerve cell dysfunction and, ultimately, nerve cell death.

The consequences of this progressive cascade include the formation of amyloid plaques, loss of brain volume, particularly in the hippocampus, and a progressive decline in cognition and the ability to function.

Recent research and clinical trials support the importance of targeting amyloid oligomers early in disease progression, including the following findings:

• Amyloid oligomer formation begins in Alzheimer’s patients years before clinical signs of the disease appear.
• Accumulation of amyloid oligomers in the brain correlates with Alzheimer’s disease progression.
• Patients with APOE4 have higher levels of amyloid oligomers compared to non-carriers, which predisposes them to increased risk and early onset of Alzheimer’s.
• Results from a recent clinical trial of BAN2401, an injectable monoclonal antibody that targets amyloid oligomers, showed reduced amyloid plaque in the brain and slowing of cognitive decline in mild Alzheimer’s patients.

We have discovered that the brain has an endogenous molecule, 3-SPA, which has potent anti-amyloid oligomer activity. 3-SPA is also the primary metabolite of tramiprosate, the active agent of ALZ-801, and, we found that its levels in the brain increased with the administration of tramiprosate in clinical trials. The endogenous nature of this major metabolite of tramiprosate may help explain the safety, excellent brain penetration and potential efficacy of ALZ-801