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New animal models of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common age-related dementia, with the number of affected individuals expected to exceed 100 million worldwide by 2050.

In Australia, Alzheimer’s disease is the third leading cause of death behind heart disease and cancer. Despite the significance of this disease there are currently no disease modifying drugs to treat Alzheimer’s disease.

The project: We have developed new transgenic C. elegans strains expressing specific disease relevant amino-truncated Aß-species.

  • The in vivo aggregation and oligomerization properties, and toxicity of these Aßx-42 transgenes will be compared.
  • C. elegans lines will be examined for rescue of the toxicity phenotypes by genetic interaction studies, to identify new therapeutic opportunities.

One of the pathological hallmarks of Alzheimer’s disease is the cerebral deposition of plaques composed of Amyloid-beta (Aß) peptide. Aß is produced by sequential proteolytic cleavage of the ubiquitously expressed integral-membrane protein, amyloid ß-protein precursor. The Aß released typically ranges from 38 to 43 amino acids in length due to imprecise cleavage. Peptides Aß1-40 and Aß1-42 are two of the most common forms and have received the majority of research attention. Clearance of Aß is slowed in cerebrospinal fluid from Alzheimer’s disease patients, which likely contributes to its pathological deposition. The accumulation of Aß is thought to lead to disease progression, however, the underlying mechanism of Aß toxicity remains unclear.

The nematode, Caenorhabditis elegans offers a simplified in vivo system in which to examine Aß toxicity and its modulation.

Figure: Staining of amyoid deposits in C. elegans. A) Controls and B) Aß1-42 expressing strain.

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