Nichols Laboratory, University of Hawai'i at Manoa

  • A N-terminal fragment (light blue) of beta amyloid is produced by cleavage of APP by the action of beta and alpha secretases. 
  • The N-terminal fragment is present in human CSF. 
          Our recent work suggests that it functions in synaptic regulation and neuroprotection.

Many years prior to the onset of Alzheimer's disease, beta amyloid (Abeta) levels in the brain rise significantly. This rise eventually triggers a cascade of events, including oxidative stress and hyperphosphorylation of tau, which lead to neurodegeneration. However, in the absence of this rise, Abeta is present at pM levels in brain, undergoing remarkable turnover. Several lines of evidence indicate that full-length Abeta at physiological levels can act as a neuromodulator. 

Having found that pM-nM Abeta regulates presynaptic calcium, largely through presynaptic nicotinic acetylcholine receptors, we investigated the structural basis for this regulation. We determined that the agonist-like action of Abeta resides in its hydrophilic N-terminal domain, narrowing the core sequence to a fragment encompassing amino acid positions 1-15/16 (light blue). This fragment has been found in human cerebrospinal fluid (CSF), indicating its presence in brain, and would result from cleavage by the beta and alpha secretases (and carboxypeptidase). Our recent work has shown that fM-pM N-terminal Abeta1-15/16 fragment is substantially more effective in regulating presynaptic calcium, augments long-term potentiation (LTP) and enhances contextual fear conditioning (CFC). Moreover, the N-terminal Abeta fragment is not toxic and protects against full-length Abeta-induced neurotoxicity, synaptic dysregulation and spatial memory deficits.

These findings raise several questions.

- How might the production of the N-terminal Abeta fragment be regulated?

- Where in brain is the N-terminal Abeta fragment produced?

- Do levels of the N-terminal Abeta fragment change over the course of Alzheimer's disease?

- Does the N-terminal Abeta fragment interact with full-length Abeta?