RECENT ADVANCES IN ALZHEIMER'S RESEARCH

[Guest guest]

Good morning NETRUMIANS and many thanks to Dr Rahman for World Alzheimer Report. Day 3 and we move into what researchers know still of the pathomechanics of AD.

Alzheimer's disease: Hypotheses

Amyloid-β toxicity at synapses

Step-wise cleavage of Amyloid Precursor Protein (APP) results in the formation of the 39 to 42 amino-acid peptide amyloid-β. Amyloid-β is prone to aggregation, giving rise to toxic species, including dimers, oligomers and fibrils. There is a consensus that synapses — in particular the postsynaptic compartment are the prime targets of amyloid-β toxicity (Selkoe 2002). Although there might be a single receptor that mediates amyloid-β toxicity at the postsynaptic compartment, it seems more likely that several postsynaptic receptors are involved, such as prion proteins, α7-nicotinergic receptors, metabotropic glutamate receptors (mGluRs) and, in particular, NMDARs (Shankar et al. 2008 ; et al. 2009). The toxicity mediated by a particular receptor may not necessarily involve direct binding of amyloid-β to the receptor, but could be due to an indirect modulation of receptor properties by amyloid-β, possibly through membrane association (THERE IS STILL A HAZE ABOUT THIS ASPECT). Excitotoxicity due to over-excitation of NMDARs has been implicated as a central mechanism by which amyloid-β causes neuronal damage, despite a lack of evidence for a direct binding of amyloid-β to NMDARs. Interestingly, NMDARs mediate amyloid-β-induced spine loss, whereas under identical experimental conditions, mGluRs mediate amyloid-β-induced LTD, suggesting that different receptors mediate different aspects of amyloid-β toxicity.

The Tale of Tau

Tau is predominantly found in axons, owing to an incompletely understood sorting mechanism. Under physiological conditions, tau has also been localized to dendrites, although levels there are much lower. The best-established functions of tau are thought to be the stabilization of microtubules and the regulation of motor-driven axonal transport (Gotz et al. 2006). Less well understood functions involve an interaction of tau with the membrane cortex. A further compartment in which tau has been found is the somatodendritic domain; tau is localized here under pathological conditions, as discussed below.

Tau has as many as 84 putative phosphorylation sites. It is more highly phosphorylated during development than in mature neurons. How phosphorylation influences tau function is only poorly understood, but it negatively regulates the binding of tau to microtubules. In patients with Alzheimer's disease tau becomes increasingly phosphorylated (that is, hyperphosphorylated) — owing to incompletely understood mechanisms — at both physiological and 'pathological' phosphorylation sites, which causes it to detach from microtubules. Hence, functions of tau that involve microtubules, such as microtubule stabilization and the regulation of axonal transport, may be compromised, possibly contributing to disease. Hyperphosphorylated tau accumulates in the somatodendritic compartment of neurons, aggregates and eventually forms neurofibrillary tangles (NFTs) There is good evidence that soluble hyperphosphorylated tau contributes to neuronal dysfunction before its deposition and has been shown to interfere with neuronal functions, such as mitochondrial respiration and axonal transport (Ittner et al. 2009).

Now we see that amyloid-β and tau exert toxicity through separate mechanisms.

So the question is where tau is to be placed in the amyloid cascade? Is it a prime target, a mediator or a kind of bystander of amyloid-β toxicity?

We find evidence from both in vitro and in vivo models that there are possible modes of interaction between the two and here is a recent hypothesis that couples the two.

Tau axis hypothesis

It incorporates the essential role of tau by defining its novel functions in dendrites and links amyloid-β and tau pathology in the dendritic compartment. This hypothesis consists of two parts.

One- postsynaptic toxicity of amyloid-β is tau-dependent. Tau interacts with tyrosine protein kinase FYN and increases targeting and/or scaffolding of FYN to the postsynaptic compartment, where FYN links NMDARs to downstream signalling pathways. This sensitizes NMDARs and makes them responsive to amyloid-β toxicity. This mode of tau-dependent amyloid-β toxicity in the dendritic compartment of neurons involves excitotoxic signalling.

Two- exposure of neurons to amyloid-β and continued exposure in particular has multiple toxic effects. I Aβ triggers progressively increased phosphorylation (hyperphosphorylation) of tau. As a consequence, tau binding to microtubules is compromised, causing tau to accumulate at an increasing pace in the somatodendritic compartment of diseased neurons. Moreover, phosphorylated tau has an increased affinity for FYN (Bhaskar et al. 2005). Together, this results in high levels of postsynaptic FYN and sensitization of NMDARs, rendering neurons even more susceptible to amyloid-β toxicity in dendrites.

And curiously enough tau reduction also prevents amyloid-β-induced defects in axonal transport of mitochondria (Vossel et al. 2010), which may link the 'tau axis hypothesis' to two additional hypotheses in the field:

Axonal transport impairment

According to which tau induces failure of axonal transport by a defined mechanism (Saper et al. 1987 ; Stamer et al 2002).

Oxidative stress

Which states mitochondria being an essential axonal transport cargo are functionally impaired, resulting in the production of reactive oxygen species (Papolla et al. 1992).

WHAT STILL REMAINS TO BE KNOWN ?????

1) There are six tau isoforms in brain. What are thier roles ? Do they act in isolation or in synergy ?

2) What is the function of tau at the membrane level ?

3) Which mechanisms determine its association with other proteins and its final targeting to specific subcellular compartments ?

4) A clear and explicit definition of the linkages between amyloid and tau.

5) What is the relationship between the levels of FYN and tau ?

There are other subsidary mechanisms which will be discussed together with the therapies- existing and putative .

REFERENCES

Bhaskar, K., Yen, S. H. & Lee, G. Disease-related modifications in tau affect the interaction between Fyn and Tau. J. Biol. Chem. 280, 35119–35125 (2005).

Götz, J., Ittner, L. M. & Kins, S. Do axonal defects in tau and amyloid precursor protein transgenic animals model axonopathy in Alzheimer's disease? J. Neurochem. 98, 993–1006 (2006)

Ittner, L. M., Ke, Y. D. & Götz, J. Phosphorylated Tau interacts with c-Jun N-terminal kinase-interacting protein 1 (JIP1) in Alzheimer disease. J. Biol. Chem. 284, 20909–20916 (2009).

, J., Gimbel, D. A., Nygaard, H. B., Gilbert, J. W. & Strittmatter, S. M. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers. Nature 457, 1128–1132 (2009).

Pappolla, M. A., , R. A., Kim, K. S. & Robakis, N. K. Immunohistochemical evidence of oxidative [corrected] stress in Alzheimer's disease. Am. J. Pathol. 140, 621–628 (1992).

Saper, C. B., Wainer, B. H. & German, D. C. Axonal and transneuronal transport in the transmission of neurological disease: potential role in system degenerations, including Alzheimer's disease. Neuroscience 23, 389–398 (1987).

Selkoe, D. J. Alzheimer's disease is a synaptic failure. Science 298, 789–791 (2002

Shankar, G. M. et al. Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nature Med. 14, 837–842 (2008).

Stamer, K., Vogel, R., Thies, E., Mandelkow, E. & Mandelkow, E. M. Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J. Cell Biol. 156, 1051–1063 (2002).

Vossel, K. A. et al. Tau reduction prevents Aβ-induced defects in axonal transport. Science 330, 198 (2010).