The Root Cause of Alzheimer’s: Amyloid-beta and Tau prions

By June 23, 2016 Commentary

The Root Cause of Alzheimer’s:  Amyloid-beta and Tau prions

ProMIS Science team’s review of the Alzheimer’s Scientific Literature

Introduction to this White Paper

ProMIS Neurosciences is focused on the discovery and development of precision treatments for neurodegenerative diseases.  Novel therapeutic candidates designed to specifically target the neurotoxic, prion-like strains of misfolded amyloid-beta peptide are being developed, based on the science of Dr. Neil Cashman, the company’s CSO, and based on the evolving body of knowledge around the pathogenesis of Alzheimer’s disease.

The goal of this document is to provide a concise overview of a growing body of scientific evidence from a number of leading researchers, much of it recent, that supports ProMIS’ strategy of selectively targeting the prion variants of Amyloid-beta and Tau. It is becoming increasingly well supported that these prion variants are the drivers of neurotoxicity, and are the drivers of the regional spreading of neurotoxicity to different areas of the brain, leading to progressive cognitive decline.   This scientific evidence also helps explain the disappointing results of previous late stage clinical programs which targeted Amyloid beta monomer or plaque.

Publications are cited in the text, and full references to each are included below.  

1)  Amyloid-Beta Plays a Causative Role in Alzheimer’s Disease

Evidence from genetic and experimental studies supports a causative role for amyloid-beta peptide (Aβ) in the pathogenesis of Alzheimer’s disease (AD).  A number of genetic studies have established a direct link between increased levels of Aβ and disease susceptibility.  Genetic mutations in the Aβ precursor protein (APP) and in the presenilin 1 and 2 genes responsible for familial forms of early onset AD all result in increased production of Aβ and Aβ aggregates (Citron et al, 1992; Borchelt et al, 1996). Down’s Syndrome patients (trisomy 21) with 3 copies of the APP gene on chromosome 21 also have elevated levels of APP and almost invariably develop Aβ deposits and AD at a premature age (Podlisny et al, 1987).  Along the same lines, the APOE4 allele linked to an increased risk of late onset AD is associated with increased Aβ deposit while the APOE2 allele linked to a decreased risk is associated with decreased Aβ levels (Holtzman et al, 2012).  Finally, the only known protective mutation against AD is found in the APP gene and leads to a reduction in the formation of Aβ (Jonsson et al, 2012).

Experimentally, intracerebral injection of Aβ-containing brain extracts from human AD patients into susceptible mice has been shown to induce cerebral amyloidosis and associated pathology. Depletion of Aβ from the extracts reversed this activity confirming the link between Aβ and disease induction (Meyer-Luehmann et al, 2006).

2)  Prion-Like Oligomers of Misfolded Aβ Mediate Neurotoxicity and Progression of Alzheimer’s Disease

While the presence of Aβ plaque is a hallmark of AD, it is now recognized that the synaptic loss and neurodegenerative spread of AD are primarily mediated by soluble oligomers of misfolded Aβ rather than plaque (Cleary et al, 2004; Jin et al, 2011).  It is believed 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 (Stohr, et al, 2012; Watts et al, 2014).  There is also evidence that such misfolded “Aβ prions” can catalyze the misfolding of Tau, another protein involved in the pathogenesis of AD (Jin et al, 2011; Choi et al, 2015).  Targeting of Aβ prions therefore represents a strategy to inhibit progression of the neurodegenerative Aβ-Tau cascade (Choi et al, 2015; Khan et al, 2014).


  • Origin of Aβ prions


The factors leading to the initial formation of misfolded Aβ oligomers remain unclear but a recent report suggests that Aβ oligomerization may represent an innate immune defense mechanism designed to entrap and neutralize invading CNS pathogens (Kumar et al, 2016).  Other factors such as the high density of Aβ in genetically susceptible individuals may also play a role in the neogenesis of Aβ prions.


  • Toxicity of Aβ prions


The direct neurotoxicity and induction of pathogenic hyperphosphorylated Tau by soluble Aβ oligomers have been demonstrated in neuronal cultures in vitro (Lauren et al, 2009; Jin et al, 2011).  In rodent models, the injection of soluble oligomeric Aβ, but not soluble monomers or plaque, was shown to induce synaptic damage and cognitive dysfunction (Cleary et al, 2005; Hong et al, 2016).  The exact mechanism responsible for Aβ oligomer toxicity is not fully understood but potential pathways include binding to cellular prion protein (PrPc) on neurons leading to synaptic dysfunction (Lauren et al, 2009) and activation of complement and phagocytic microglia leading to synaptic loss (Hong et al, 2016).

3)  Involvement of Aβ prions in Spatial Propagation of Neurodegeneration

A convergence of evidence from multiple studies suggests that the progressive nature of AD arises from the formation and spread of Aβ prions, a subset of misfolded oligomers of Aβ that adopt a β−sheet-rich conformation transmissible to native Aβ in a template-like manner.  The self-propagation of these Aβ prions follows the stereotypical progression of AD with initial involvement of the enthorhinal cortex followed by spreading to the hippocampus and neocortex (Khan et al, 2014).

The prion-like spread of Aβ oligomers is well-documented in animal models following the injection of purified oligomers or brain extracts from AD patients or diseased animals (Cleary et al, 2005; Meyer-Luehmann et al, 2006; Watts et al, 2014; Hong et al, 2016).  Notably, Watts et al showed that intracerebral inoculation of susceptible transgenic mice with extracts from the brain of sporadic or heritable Artic and Swedish AD cases resulted in accelerated Aβ aggregation and replicated the characteristic pathologies observed in the human donors.  Importantly, the disease phenotypes were preserved upon serial passage from mouse to mouse supporting the existence of distinct pathogenic Aβ prion strains with “locked in” configurations (Watts et al, 2014).   

4)  Rationale for a Therapeutic Antibody-Based Approach

Targeting of pathogenic Aβ prions and associated propagation of misfolding lends itself to an antibody-based approach as opposed to small molecule approaches which have largely proven to be ineffective at inhibiting protein-protein interactions.  The selective targeting of Aβ prions offers distinct advantages over the more broadly reactive Aβ antibodies currently in clinical testing.  Specific neutralization of Aβ prions is expected to maximize efficacy by avoiding binding to non-pathogenic Aβ monomers or Aβ plaque which can act as a “sink” for antibodies binding these forms.  Preservation of normal Aβ function as well as a decrease in the risk of edema and vascular adverse effects associated with the engagement of plaque (Sevigny et al, 2015) should also contribute to a more favorable safety profile.

One potential drawback of an antibody therapy is the expected low level of penetrance across the blood-brain-barrier which has been reported to be on the order of 0.1-1% of circulating levels.  However, the regional increase in blood-brain-barrier leakiness observed in AD patients should increase local exposure in the affected areas (van de Haar et al, 2016).  The imaging evidence for plaque clearance and CNS side effects observed in recent trials of Aβ monoclonal antibodies are also indicative of CNS penetrance (Sevigny et al, 2015).  Finally, systemic delivery of antibodies, as well as active immunization with disease-relevant antigens in animal models, have also been shown to result in local therapeutic effects in the CNS (Meyer-Luehmann et al, 2006).

5) The ProMIS Platform

ProMIS Neurosciences has developed two proprietary computational discovery technologies, ProMISTM and Collective Coordinates, to predict regions of protein most likely to unfold based on thermodynamic stability.  The output provides potential disease-specific epitopes unique to misfolded protein species which can be used to generate antibodies for testing.  

In the AD program, 6 predicted disease-specific epitopes of Aβ prions have been identified. Antibodies have been raised against 5 of the epitopes and are currently undergoing screening and validation for prion specific binding and functional activity.  

This concept has already been applied to SOD1 prions involved in the pathology of ALS.  Antibodies against predicted SOD1disease-specific epitopes were generated and shown to inhibit in vitro transmission of pathogenic SOD1 prions (Grad et al, 2014) as well as provide a benefit in animal models of ALS.



Borchelt, D.R. et al (1996) Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron 17: 1005-1013

Choi, S.H. et al (2015) Recapitulating amyloid beta and Tau pathology in human neural cell culture models – Clinical implications.  US Neurology 11: 102-105

Citron, M. et al (1992) Mutation of the beta-amyloid precursor protein in familial Alzheimer’s disease increases beta-protein production. Nature 360: 672-674

Cleary, J.P. et al (2005) Natural oligomers of the amyloid-b protein specifically disrupt cognitive function.  Nature Neuroscience 8: 79-84

Grad, L.I. et al (2014) Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and –independent mechanisms. Proc Natl Acad Sci 111: 3620-3625  

Holtzman, D.M., Herz, J. and Bu, G. (2012) Apolipoprotein E and Apolipoprotein E receptors: Normalbiology and rolwes in Alzheimer disease, Cold Spring Harb Perspect Med, 2, a006312

Hong S. et al (2016) Complement and microglia mediate early synapse loss in Alzheimer mouse models.  Science 352: 712-716

Jin, M. et al (2011) Soluble amyloid b-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci 108: 5819-5824

Jonsson, T. et al (2012) A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488: 96-99

Khan, U.A. et al (2014) Molecular drivers and cortical spread of lateral enthorhinal cortex dysfunction in preclinical Alzheimer’s disease. Nature Neuroscience 17: 304-313

Kumar, D.K.V. et al. (2016) Amyloid beta peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Science Translational Med. 8: 340ra72

Lauren, J. et al (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-b oliogmers, Nature 457: 1128-1134

Meyer-Luehmann, M. et al (2006) Exogenous induction of cerebral b-amyloidogenesis is governed by agent and host. Science 313: 1781-1784

Podlisny, M.B., Lee, G. and Selkoe D.J. (1987) Gene dosage of the amyloid beta precursor protein in Alzheimer’s disease. Science 238: 669-671

Sevigny, J. et al (2015) Aducanumab (BIIB037), an anti-amyloid beta monoclonal antibody, in patients with prodromal or mild Alzheimer’s disease: interim results of a randomized, double-blind, placebo-controlled, Phase 1B study. Alzheimer’s & Dementia, 11: Suppl P277

Stohr, Jan, et al (2012) Purified and synthetic Alzheimer’s amyloid beta (Aβ ) prions Proc Natl Acad Sci  109: 11025-11030

Van de Haar, H.J. et al (2016) Blood-brain barrier leakage in patients with early Alzheimer disease. Radiology, published online ahead of print: 10.1148/radiol.2016152244

Watts, J.C. et al (2014) Serial propagation of distinct strains of Abeta prions from Alzheimer’s disease patients. Proc Natl Acad Sci  111: 10323-10328