Alzheimer’s Disease

Key Investigators: Jesse Wiley, Mark Bothwell

For more than two decades, basic and clinical research in Alzheimer’s disease (AD) has been dominated by adherence to the amyloid cascade hypothesis, which attributes disease causation to accumulation of aggregates of toxic amyloid peptides produced by sequential cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase enzymes. Seemingly compelling evidence for this hypothesis includes evidence that familial forms of AD result from mutations of APP or of gamma-secretase subunits presenilin-1 or presenilin-2.

However, contrary to this hypothesis, we have shown that familial AD mutations of APP and presenilins generally inhibit gamma-secretase-mediated cleavage of APP rather than increasing cleavage, and studies of AD brains at autopsy reveal elevated levels of intact APP, despite reduced levels of APP mRNA, suggesting that secretase-mediated processing in AD is abnormally low, not abnormally high. Further, recent clinical trials of antibodies that virtually eliminate amyloid deposits from the brain have failed to demonstrate any significant benefit to cognition.

Abandoning the Amyloid Cascade Hypothesis

We suggest that the solution to this conundrum lies in recognizing that APP has important signaling functions for which amyloid peptide production is irrelevant. We were among the first to point out that APP participates in Notch-like signaling functions, controlled, in part, by gamma-secretase-mediated intracellular release of APP’s intracellular domain. We are presently investigating a novel mechanism by which intact membrane-resident APP may impair transcriptional signaling pathways.

Some of our AD-related publications

  1.    M. Bothwell, E. Giniger, Alzheimer’s disease: neurodevelopment converges with neurodegeneration. Cell 102, 271–273 (2000).
  2.    J. C. Wiley, E. A. Smith, M. P. Hudson, W. C. Ladiges, M. Bothwell, Fe65 stimulates proteolytic liberation of the beta-amyloid precursor protein intracellular domain. J Biol Chem 282, 33313–33325 (2007).
  3.    J. C. Wiley, M. Hudson, K. C. Kanning, L. C. Schecterson, M. Bothwell, Familial Alzheimer’s disease mutations inhibit gamma-secretase-mediated liberation of beta-amyloid precursor protein carboxy-terminal fragment. J. Neurochem. 94, 1189–1201 (2005).
  4.    J. C. Wiley, et al., Phenylbutyric acid rescues endoplasmic reticulum stress-induced suppression of APP proteolysis and prevents apoptosis in neuronal cells. PLoS ONE 5, e9135 (2010).
  5.    R. de Laat, et al., LINGO-1 promotes lysosomal degradation of amyloid-β protein precursor. Pathobiol. Aging Age Relat. Dis. 5, 25796 (2015).