Identification of a novel Alzheimer’s disease pathway provides potential new avenues for drug discovery

 

Neurofibrillary tangle.

Neurofibrillary tangle.

In August and September of 2012, we published three articles on Alzheimer’s disease on the Biopharmconsortium Blog:

Subsequent to the publication of our articles–on 21 November, 2012–the Wellcome Trust announced the identification of a novel pathway involved in the pathogenesis of Alzheimer’s disease (AD). This research was led by Professor Simon Lovestone and Dr Richard Killick (Kings College, London U.K.), and was published in the online edition of Molecular Psychiatry on 20 November 2012. The Wellcome Trust helped to fund the research.

As we have discussed in earlier articles on this blog, the dominant paradigm among AD researchers and drug developers is that the disease is caused by aberrant metabolism of amyloid-β (Aβ) peptide, resulting in accumulation of neurotoxic Aβ plaques. This paradigm is known as the “amyloid hypothesis”. AD is also associated with neurofibrillary tangles (NFTs) which are intracellular aggregates of hyperphosphorylated tau protein. In contrast to the amyloid hypothesis, some AD researchers have postulated that NFT formation is the true cause of AD. The new research links amyloid toxicity to the formation of NFTs, and identifies potential new drug targets.

The new study is based on the discovery of the role of clusterin–an extracellular chaperone protein–in sporadic (i.e., late-onset, non-familial) AD. The gene for clusterin, CLU, has been identified as a genetic risk factor for sporadic AD via a genome-wide association study published in 2009. Clusterin protein levels are also increased in the brains of transgenic mouse models of AD that express mutant forms of amyloid precursor protein (APP), as well as in the serum of humans with early stage AD.

The researchers first studied the relationship between Aβ and clusterin in mouse neuronal cells in culture. Aβ rapidly increases intracellular concentrations of clusterin in these cells. Aβ-induced increases in clusterin drives transcription of a set of genes that are involved in the induction of tau phosphorylation and of Aβ-mediated neurotoxicity. This pathway is dependent on the action of a protein known as Dickkopf-1 (Dkk1), which is an antagonist of the cell-surface signaling protein wnt. The transcriptional effects of Aβ, clusterin, and Dkk1 are mediated by activation of the wnt-planar cell polarity (PCP) pathway. Among the target genes in the clusterin-induced DKK1-WNT pathway that were identified by the researchers are EGR1 (early growth response-1), KLF10 (Krüppel-like factor-10) and NAB2 (Ngfi-A-binding protein-2)–all of these are transcriptional regulators. These genes are necessary mediators of Aβ-driven neurotoxicity and tau phosphorylation.

The researchers went on to show that transgenic mice that express mutant amyloid display the transcriptional signature of the DKK1-WNT pathway, in an age-dependent manner, as do postmortem human AD and Down syndrome hippocampus. (Most people with Down syndrome who survive into their 40s or 50s suffer from AD.) However, animal models of non-AD tauopathies (non-AD neurodegenerative diseases associated with pathological aggregation of tau, and formation of NFTs, but no amyloid plaques) do not display upregulation of transcription of genes involved in the DKK1-WNT pathway, nor does postmortem brain tissue of humans with these diseases.

The Kings College London researchers concluded that the clusterin-induced DKK1-WNT pathway may be involved in the pathogenesis of AD in humans. They also hypothesize that such strategies as blocking the effect of Aβ on clusterin or blocking the ability of Dkk1 to drive Wnt–PCP signaling might be fruitful avenues for AD drug discovery. According to the Wellcome Trust’s 21 November 2012 press release, Professor Lovestone and his colleagues have shown that they can block the toxic effects of amyloid by inhibiting DKK1-WNT signaling in cultured neuronal cells. Based on these studies, the researchers have begun a drug discovery program, and are at a stage where potential compounds are coming back to them for further testing.

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