• 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 the N-terminal fragment functions in synaptic regulation and neuroprotection

             A core sequence encompassing the essential residues within the N-terminal fragment for neuromodulation and neuroprotection has been identified: YEVHHQ

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 within 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 pM N-terminal Abeta1-15/16 fragment is substantially more effective than full-length Abeta in regulating presynaptic calcium, augmenting long-term potentiation (LTP) and enhancing 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 in in vitro, ex vivo and in vivo models. The hexapeptide core (AbetaCore) replicates the action of the N-terminal Abeta fragment.

These findings raise several questions.

- By what mechanisms do the N-terminal Abeta fragments protect against Abeta-linked synaptic dysfunction and neurotoxicity?

- Do the N-terminal Abeta fragments regulate Abeta-linked gliotoxicity?

NEWS:

Congratulations to Ruth on passing her PhD defense!

Congratulations to Megan, Alyssa and Donovan on the publication of their paper in the Journal of Neuroinflammation

(9.59 - 2-year Impact Factor)       SharedIt link:  https://rdcu.be/dc9Fr

Congratulations to Donovan for defending his MS thesis and graduating! 

Congratulations to Kendra for defending her MS thesis and graduating!

Also: "To Qatar, with Aloha" in UH Med Now: https://jabsom.hawaii.edu/to-qatar-with-aloha/

Congratulations to Dr. Megan for defending her PhD dissertation and graduating!

Also: Highlight in UH Med Now: https://jabsom.hawaii.edu/despite-pandemic-jabsom-phd-grad-successfully-juggled-new-motherhood-and-

scientific-research/

Congratulations to Alyssa on achieving Honors with her Bachelor's and starting at JABSOM!

Congratulations to Kelly, Ruth and Komal on the publication of their paper in Frontiers in Molecular Neuroscience