Critical Insight: Toxic soluble Amyloid beta oligomers (“prions”), not plaque, drive pathogenesis in Alzheimer’s disease

By October 4, 2016Commentary

Critical Insight:  Toxic soluble Amyloid beta oligomers (“prions”), not plaque, drive pathogenesis in Alzheimer’s disease

Refinement of the Amyloid beta cascade hypothesis – Prions vs. Plaque

The presence of Amyloid beta (Aβ) plaque is a hallmark of Alzheimer’s disease (AD) and several clinical trials have been undertaken to reduce or clear plaque from the brain of affected patients. Hardy & Higgins originally postulated in 1992 that, in susceptible individuals, excess Aβ monomers aggregate into larger oligomers that then go on to form fibrils and ultimately plaque deposits which are responsible for neurotoxicity and atrophy1.   

However, since then, a mounting body of experimental and clinical evidence has shown that soluble toxic Aβ oligomers, and not plaque, are actually the primary drivers of neurodegeneration and cognitive decline in AD patients. Histological and imaging studies clearly show that synaptic loss and memory impairment correlate poorly with plaque burden in both human and mouse AD2,3.  Perhaps more directly, Aβ insoluble fibrils and Aβ monomers have shown little or no demonstrable toxicity in vitro or in vivo4-6 while soluble Aβ oligomers have demonstrated a high degree of neurotoxicity and induction of cognitive impairment.4-9 Recent work further indicates that a subset of misfolded Aβ oligomers can propagate in a prion-like manner and form a seed or template capable of converting surrounding Aβ into the toxic oligomer form, representing the “true” culprit in AD pathogenesis.10,11

Lessons from clinical trials

Clinical trials testing Aβ antibodies with different binding profiles (monomers vs. oligomers vs. plaque) have yielded important information: the evidence shows that antibodies administered systemically can cross the blood-brain-barrier in limited but sufficient amounts to have local central nervous system (CNS) effects. This is clearly demonstrated by the reduction in plaque burden reported in a recent publication of the results from the aducanumab “PRIME” clinical trial completed in 2015.12  

An encouraging signal for the slowing of cognitive decline was also observed in this trial and was widely attributed to plaque clearance in the ensuing press coverage, perhaps driven by the title of the publication: “The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease”.  However, the thorough analysis presented in the article goes well beyond the title and presents a picture consistent with the latest scientific thinking on the role of toxic oligomers.12  

In agreement with the current understanding of AD pathogenesis, the investigators on the aducanumab study state that “The apparent clinical benefit observed in PRIME could also be explained by the binding of aducanumab to oligomeric forms of Aβ, which would not be directly detected by PET imaging. The reductions in standardized uptake value (SUVR) scores may be surrogates for reductions in toxic Aβ oligomers which may have had a more functionally relevant impact on cognition.”12 Indeed, recent structural studies presented by Biogen at the Alzheimer’s Association International Conference (AAIC) in July 201613 demonstrate the selectivity of aducanumab for oligomers and its lack of binding to monomers, the latter representing a potential “sink” for antibodies which can act to reduce the effective dose. Binding to plaque can also diminish the specific activity of the antibody and represents a liability as disruption of plaque was associated with dose-dependent adverse events (brain edema – ARIA-E), likely caused by the induction of inflammation and/or release of toxic oligomers sequestered in plaque.4,12,14

Optimal target profile for Aβ antibodies

The weight of the currently available experimental and clinical data favors selective targeting of soluble toxic oligomers or prion variants of Aβ as the primary drivers of AD pathogenesis.  Specific neutralization of Aβ prions is expected to maximize efficacy by avoiding unproductive binding to non-pathogenic Aβ monomers or Aβ plaque as well as decrease the risk of

edema and vascular adverse effects associated with plaque engagement. None of the Aβ antibodies currently under study specifically targets toxic oligomers.

ProMIS utilizes complementary computational algorithms, ProMISTM and Collective Coordinates, to predict structurally integral misfolding and identify disease-specific epitopes in Aβ and other misfolded prion-like proteins (e.g. Tau, SOD1, TDP43).  

Using this method, six distinct disease-specific epitopes (targets) were identified for Aβ. Generation of monoclonal antibodies against the first three epitopes yielded candidates with the desired target profile of selective binding to soluble toxic oligomers or “prions” from AD brain extracts, with little or no binding to monomers or to plaque in AD brain tissue. The antibodies also detect a signal in cerebrospinal fluid (CSF), raising the possibility of patient-specific precision therapy. Analysis of antibodies against the other three epitopes is ongoing.  

References

  1. Hardy, JA & Higgins, GA (1992) Alzheimer’s disease: The amyloid cascade hypothesis.  Science 256:  184-185
  2. Jacobsen, JS et al (2006) Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease.  PNAS 103: 5161-5166
  3. Brier, MR et al (2016) Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease.  Science Trans Med 8:  pp 338ra66
  4. Shankar, GM et al (2008) Amyloid-β protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory.  Nat Med 14: 837-842
  5. Cleary, JP et al (2005) Natural oligomers of the amyloid-β protein specifically disrupt cognitive function.  Nature Neuroscience 8: 79-84
  6. Hong, S et al (2016) Complement and microglia mediate early synapse loss in Alzheimer mouse models.  Science 352:  712-716
  7. Lacor, PN et al (2007) Aβ oligomer-induced aberrations in synapse composition, shape and density provide a molecular basis for loss of connectivity in Alzheimer’s disease.  J Neuroscience 27: 796-807.
  8. Jin, M et al (2011) Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. PNAS 108: 5819-5834
  9. Lauren, J et al (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers.  Nature 457: 1128-1132
  10. Stohr, J et al (2012) Purified and synthetic Alzheimer’s amyloid beta (Aβ) prions.  PNAS 109: 11025-11030
  11. Watts, JC et al (2014) Serial propagation of distinct strains of Abeta prions from Alzheimer’s disease patients.  PNAS 111: 10323-10328
  12. Sevigny J et al (2016) The antibody aducanumab reduces Aβ plaque in Alzheimer’s disease.  Nature 537:  50-56
  13. Arndt, JW et al (2016) Structural basis of unique selectivity of aducanumab for aggregated forms of amyloid-β.  Poster P1-167, AAIC 2016
  14. Fuller, JP et al (2015) Comparing the efficacy and neuroinflammatory potential of three anti-abeta antibodies.  Acta Neuropathol 130: 699-711