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Paradigm Shift in Alzheimers´s Research opens the Door for New Treatments

16.10.2007
Intraneural Aß aggregation triggers neuron loss

Latest research by Professor Thomas Bayer from University Medicine Center Göttingen carries the promise of developing new treatments.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by extensive neuronal degeneration and the development of neuritic amyloid plaques and neurofibrillary tangles. Neuronal and synaptic losses in AD are correlated with dementia and occur in specific brain areas involved in memory processing.

Long-standing evidence shows that progressive cerebral deposition of Aß plays a seminal role in the pathogenesis of AD. There is great interest, therefore, in understanding the proteolytic processing of APP, the precursor of Aß, and its proteases responsible for generating Aß. Ragged peptides with a major species beginning with phenylalanine at position 4 of Ab have been reported already in 1985 by Masters et al.1.

In 1992, Mori et al. first described the presence of AßN3(pE) using mass spectrometry of purified Aß protein from AD brains, which explains the difficulties in sequencing the amino-terminus2. They reported that only 10-15% of the total Aß isolated by this method begins at position 3 with AßN3(pE). Later it became clear that AßN3(pE) represents a dominant fraction of Aß peptides in AD and Down’s syndrome brain3-15.

N-terminal deletions in general enhance aggregation of ß-amyloid peptides in vitro16. AßN3(pE) has a higher aggregation propensity17,18, and stability19, and shows an increased toxicity compared to full-length Aß20. In AD only a small proportion of Aß starts at position 1 with L-aspartate in plaques (~10%), and this fraction is higher in vascular amyloid (~65%). In plaques, ~50% of the amyloid starts at position 3 in the form of AßN3(pE), whereas in the vascular amyloid, this form accounts for only 11%5.

A comparison between amyloid peptides of cognitively normal elderly people and AD patients showed that soluble amyloid aggregates are different between these groups. In AD the major Aß species started with N3(pE) and ended at the C-terminus at position 4211.

Neuropathological features

To identify the molecular mechanisms that lead to AD-typical neuropathological hallmarks transgenic mouse models proved to be a valuable tool. We have been characterizing the APP/PS1KI mouse model that closely mimics the development of AD related neuropathological features including a significant neuronal loss in the hippocampus, a structure involved in learning and memory processes21. Specific neurodegeneration in the hippocampal CA1 subfield and entorhinal cortex is an early event in the AD pathology that correlates directly with the severity of the disease22. As in post-mortem AD brain, it has been demonstrated that the APP/PS1KI mouse model harbours abundant N-modified Aß42 including AßN3(pE). We therefore used this model to study a possible link between accumulation of AßN3(pE) and down-stream AD-typical pathological events. This transgenic mouse model carries M233T/L235P knocked-in mutations in presenilin-1 and overexpresses mutated human ß-amyloid precursor protein. Aßx-42 is the major form of Aß species present in this model with progressive development of a complex pattern of N-truncated variants and dimers, similar to those observed in AD brain.

At the age of six months an age-dependent significant reduced ability to perform working memory and motoric tasks is seen in these mice. The APP/PS1KI mice were smaller and showed development of a thoralumbar kyphosis, together with reduced body weight, and axonal degeneration in brain and spinal cord23. At six months of age already a 33% CA1 neuron loss in the hippocampus, together with a drastic reduction of long-term potentiation was observed24.

CA1 neuron loss in these mice is likely to contribute to the working memory deficits and complete loss of synaptic plasticity (long-term potentiation) after stimulation of the Schaffer collaterals. Intraneuronal Aß and peptides beginning with aspartate at position 1, and pyro-glutamate at position 3 were detected as early as two months of age. Accumulation increased significantly at the age of six months. Of all Aß peptides studied, the peptide that starts with pyro-glutamate (AßN3(pE)) at position 3 showed the highest increase in accumulation in neurons by 435%.

At 10 months of age, an extensive neuronal loss (>50%) is present in the CA1/2 hippocampal pyramidal cell layer that correlates with strong accumulation of intraneuronal Aß and thioflavine-S-positive intracellular material but not with extracellular Aß deposits. A strong reactive astrogliosis develops together with the neuronal loss.

Cholinergic deficits

Moreover, we have studied the neuron loss in different cholinergic nuclei and found that cholinergic neurons degenerate as a function of intraneuronal AßX-42 accumulation. This finding may explain cholinergic deficits in AD patients and indicates that cholinergic dysfunction is a down-stream event in AD pathology.

In addition, complete loss of neurogenesis in the dentate gyrus in APP/PS1KI mice points to a degenerative mechanism, which is independent from intracellular Aß aggregation. No intracellular Aß was detected in these neurons. The reduced number of dentate gyrus neurons (-30% at six months of age) may be at least partly a function of loss of neurogenesis.

Clinical implications

•Overall, this mouse model develops a robust neuronal dysfunction and degeneration, which triggers AD-typical changes on different levels including synaptic plasticity and working memory.

•The neuron loss in different brain areas mostly follows the pattern of intraneuronal AßX-42 accumulation.

•From these observations we conclude that intraneuronal AßX-42 accumulation is the major neurotoxic factor in AD etiology.

•Of special interest is that pyro-glutamate-Aß42 is the variant, which aggregates fastest in degenerating neurons. This is likely due to its enhanced stability and propensity to aggregate.

•Therefore, this peptide most likely seems to be responsible for the observed neuronal toxicity.

The prevention of pyro-glutamate Aß aggregation is therefore an important mechanism and therapeutic target.

References

1.Masters, C.L., et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 82, 4245-4249 (1985).
2.Mori, H., Takio, K., Ogawara, M. & Selkoe, D.J. Mass spectrometry of purified amyloid beta protein in Alzheimer's disease. J Biol Chem. 267, 17082-17086. (1992).
3.Saido, T.C., Yamao-Harigaya, W., Iwatsubo, T. & Kawashima, S. Amino- and carboxyl-terminal heterogeneity of beta-amyloid peptides deposited in human brain. Neurosci Lett 215, 173-176 (1996).
4.Saido, T.C., et al. Dominant and differential deposition of distinct beta-amyloid peptide species, A beta N3(pE), in senile plaques. Neuron 14, 457-466 (1995).
5.Kuo, Y.M., Emmerling, M.R., Woods, A.S., Cotter, R.J. & Roher, A.E. Isolation, chemical characterization, and quantitation of A beta 3-pyroglutamyl peptide from neuritic plaques and vascular amyloid deposits. Biochem Biophys Res Commun 237, 188-191. (1997).
6.Kuo, Y.M., et al. Comparative analysis of amyloid-beta chemical structure and amyloid plaque morphology of transgenic mouse and Alzheimer's disease brains. J Biol Chem 276, 12991-12998 (2001).
7.Hosoda, R., et al. Quantification of modified amyloid beta peptides in Alzheimer disease and Down syndrome brains. J Neuropathol Exp Neurol 57, 1089-1095 (1998).
8.Harigaya, Y., et al. Amyloid beta protein starting pyroglutamate at position 3 is a major component of the amyloid deposits in the Alzheimer's disease brain. Biochem Biophys Res Commun 276, 422-427. (2000).
9.Iwatsubo, T., Saido, T.C., Mann, D.M., Lee, V.M. & Trojanowski, J.Q. Full-length amyloid-beta (1-42(43)) and amino-terminally modified and truncated amyloid-beta 42(43) deposit in diffuse plaques. Am J Pathol 149, 1823-1830. (1996).
10.Miravalle, L., et al. Amino-Terminally Truncated Abeta Peptide Species Are the Main Component of Cotton Wool Plaques. Biochemistry 44, 10810-10821. (2005).
11.Piccini, A., et al. {beta}-Amyloid Is Different in Normal Aging and in Alzheimer Disease. J. Biol. Chem. 280, 34186-34192 (2005).
12.Piccini, A., et al. Association of a Presenilin 1 S170F Mutation With a Novel Alzheimer Disease Molecular Phenotype. Arch Neurol. 64, 738-745. (2007).
13.Russo, C., et al. Heterogeneity of water-soluble amyloid beta-peptide in Alzheimer's disease and Down's syndrome brains. FEBS Lett 409, 411-416. (1997).
14.Guntert, A., Dobeli, H. & Bohrmann, B. High sensitivity analysis of amyloid-beta peptide composition in amyloid deposits from human and PS2APP mouse brain. Neuroscience. 143, 461-475 (2006).
15.Tekirian, T.L., et al. N-terminal heterogeneity of parenchymal and cerebrovascular Abeta deposits. J Neuropathol Exp Neurol 57, 76-94. (1998).
16.Pike, C.J., Overman, M.J. & Cotman, C.W. Amino-terminal Deletions Enhance Aggregation of beta-Amyloid Peptides in Vitro. J. Biol. Chem. 270, 23895-23898 (1995).
17.He, W. & Barrow, C.J. The A beta 3-pyroglutamyl and 11-pyroglutamyl peptides found in senile plaque have greater beta-sheet forming and aggregation propensities in vitro than full-length A beta. Biochemistry. 38, 10871-10877. (1999).
18.Schilling, S., et al. On the seeding and oligomerization of pGlu-amyloid peptides (in vitro). Biochemistry. 45, 12393-12399. (2006).
19.Kuo, Y.M., Webster, S., Emmerling, M.R., De Lima, N. & Roher, A.E. Irreversible dimerization/tetramerization and post-translational modifications inhibit proteolytic degradation of A beta peptides of Alzheimer's disease. Biochim Biophys Acta 1406, 291-298 (1998).
20.Russo, C., et al. Pyroglutamate-modified amyloid -peptides - A N3(pE) - strongly affect cultured neuron and astrocyte survival. Journal of Neurochemistry 82, 1480-1489 (2002).
21.Casas, C., et al. Massive CA1/2 Neuronal Loss with Intraneuronal and N-Terminal Truncated A{beta}42 Accumulation in a Novel Alzheimer Transgenic Model. Am J Pathol 165, 1289-1300. (2004).
22.West, M.J., Coleman, P.D., Flood, D.G. & Troncoso, J.C. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease. Lancet 344, 769-772. (1994).
23.Wirths, O., Breyhan, H., Schafer, S., Roth, C. & Bayer, T.A. Deficits in working memory and motor performance in the APP/PS1ki mouse model for Alzheimer's disease. Neurobiol Aging 8, 8 (2007). doi:10.1016/j.neurobiolaging.2006.12.004.

24.Wirths, O., Weis, J., Kayed, R., Saido, T.C. & Bayer, T.A. Age-dependent axonal degeneration in an Alzheimer mouse model. Neurobiol Aging 8, online version (2006). doi:10.1016/j.neurobiolaging.2006.07.021.

Maria Vrijmoed-de Vries | alfa
Further information:
http://www.ecnp.eu

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