Alzheimer's Disease and Frontotemporal Dementias

	Pin1 protein has been shown to have an involvement in plaque formation (as well as tangles)
	Davies et al. (2000) suggested that pathogenic changes to APP and tau might both be triggered by a single underlying event: the phosphorylation of threonine 231 on tau results in a conformation that is strikingly similar to phosphorylation of threonine 668 on APP. (N.B. You can read the news report I read via the 'Virtual Conferences' link on the Alzheimer's Research Forum website .)
	They also reported that this phosphorylated site on APP rendered it a target for Pin1. Additionally, immunostaining of AD brain tissues with monoclonal antibodies showed that the pThr 668 APP occured in the lysosomal compartment of hippocampal and cortical neurons, and only in those neurons which were also positive for pThr 231 tau. Importantly, it was speculated that Pin1 binding to APP might result in increased beta-amyloid formation.
	Ramelot and Nicholson (2001) have subsequently published work using NMR spectroscopy to shed new light on the interactions of the cytoplasmic tail of APP (APPc) with intracellular signalling and beta-amyloid peptide proteolytic factors.

	The serine residue at 655 and the threonine residues at 654 and 668 are known to be phosphorylated in vivo and may be involved with regulating these interactions. These authors results showed backbone dihedral angle changes symptomatic of hydrogen bond formation.
	The biggest conformational change occurred upon phosphorylation of the (neuron-specific phosphorylation site) Thr 668 (see Davies et al. above) and it was suggested that this phosphorylation may therefore act as a conformational switch altering the specificity and affinity of APP binding to its cytosolic partner proteins (see similar conclusions drawn by Zhou et al., 2000 for tau and Cdc25C ).
	They concluded that the most likely candidate kinase for this phosphorylation in vivo was cdk5 . Their results showed that the unphosphorylated T668 is in a stable trans conformation and that its phosphorylation produced an equilibrium of cis and trans isomers.
	They proposed a model whereby this latter could initiate a regulatory mechanism in which cytosolic binding factors were isomer-specific.
	This opens up a situation whereby the isomerase action of Pin1 could mediate increased APP proteolysis by trans-conformation specific secretases (in similar manner to the trans-conformation specific dephosphorylation of tau and Cdc25C by PP2A [Zhou et al., 2000).

Comment for ARF upon ‘Pastoriono L et al. The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-b production. Nature 440: 528-534’

Julian Thorpe

KP Lu‘s group and his collaborators have been at the fore of elucidating Pin1’s cellular roles, including, since discovering that tau is a Pin1 target protein, its involvement in neurodegeneration. On the basis of their accumulated data that depletion of Pin1 causes apoptosis in HeLa cells, that patterns of AD pathology correlate with regions of lower Pin1 expression in normal human brain, that Pin1 knockout mice suffer neurodegeneration and that Pin1 can ameliorate p-tau pathology, they have suggested that a fuller elucidation of Pin1’s involvement in neurodegeneration (and cancer) might lead to new therapeutic strategies.

Our group has acquired data confirmatory of, and complementary to, that of Lu and his co-workers. We have observed Pin1 deficits in a range of frontotemporal dementias and in ageing normal brain neurons and have suggested that this might be a susceptibility factor both in neurodegenerative disease (Thorpe et al., 2004) and in ageing-related neurodegeneration (Hashemzadeh-Bonehi et al., In Press).

In this latest work, Lu and colleagues suggest that deficits of Pin1 would also be deleterious to neurons in respect of Ab secretion; it binds to p-Thr668 of APP and its overexpression reduces Ab secretion in cell cultures, whilst knockdown, both in cells and mice, selectively increases secretion of the toxic amyloid species, Ab42. A concern is that this data is contradictory to the work of others (Akiyama et al., 2005), which is not referred to in this present work. Akiyama et al. also used knockdown mice and several cell lines (different to those used by Lu et al.). I can only presume that differences in genetic background might account for the discrepant data between these two studies; although the source of the Pin1 KO mouse is the same for both groups, it appears that Lu's group maintain their colony in an inbred C57/S129 line, whereas Akiyama’s group maintain a C57/B6 strain. Clear differences have been observed in these strains’ behavioural phenotypes. Additionally, the mouse brain gene expression database shows higher hippocampal Gsk3b expression in an S129-derived strain than in a C57/B6 strain. Such strain differences, especially local concentrations of upstream APP kinases, could influence APP processing. Indeed, the elucidation of these differences might add important new insights into the neurodegenerative process.

Whilst research showing involvements of just one specific protein in molecular neuropathological pathways do not confirm their centrality to a disease, other recent research evidence is supportive of such a view: Pin1 promoter polymorphisms, which result in lowered protein expression, correlate with AD (Segat et al., In Press) and Pin1 is one of a handful of proteins susceptible to oxidation in MCI hippocampus, with the authors suggesting that this may be involved in the progression from MCI to AD (Butterfield et al., In Press). Thus, if the concern re conflicting data above is addressed, this new data from Lu’s group could put Pin1 protein potentially at the heart of the ameliorative influences that might slow or halt the key twin molecular neuropathological pathways leading to plaque and tangle formation and thence neuronal cell death in AD.

References:

Akiyama H, Shin R-W, Uchida C, Kitamtoto T, Uchida T(2005) Pin1 promotes production of Alzheimer's amyloid b from b-cleaved amyloid precursor protein. Biochemical and Biophysical Research Communications 336: 521-529

Butterfield DA, Poon HF, Clair DSt, Keller JN, Pierce WM, Klein JB, Markesbery WR (In Press) Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: Insights into the development of Alzheimer's disease. Neurobiology of Disease

Hashemzadeh-Bonehi L, Phillips RG, Cairns NJ, Mosaheb S, Thorpe JR (In Press) Pin1 protein associates with neuronal lipofuscin: potential consequences in age-related neurodegeneration. Experimental Neurology

Segat L, Pontillo A, Annoni G, Trabattoni D, Vergani C, Clerici M, Arosio B, Crovella S (In Press) Pin1 promoter polymorphisms are associated with Alzheimer's disease. Neurobiology of Aging

Thorpe JR, Mosaheb S, Hashemzadeh-Bonehi L, Cairns NJ, Kay KE, Morley SJ, Rulten S (2004) Shortfalls in the Peptidyl-Prolyl Cis-Trans Isomerase Protein Pin1 in Neurons are Associated With Frontotemporal Dementias. Neurobiology of Disease 17: 237-249

Diagram of Possible Pin1 Involvement in Plaque Formation References

References

And see: Akiyama H, Shin R-W, Uchida C, Kitamtoto T, Uchida T(2005) Pin1 promotes production of Alzheimer's amyloid b from b-cleaved amyloid precursor protein. Biochemical and Biophysical Research Communications 336: 521-529

For diagram above:

(1) Cataldo, AM, Peterhoff, CM, Troncosco, JC, Gomez-Isla, T, Hyman, BT and Nixon, RA (2000) Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome - Differential effects of APOE genotype and presenilin mutations. American Journal Of Pathology 157: 277-286

(2) Gerez L, Mohrmann K, van Raak M, Jongeneelen M, Zhou XZ, Lu KP and van der Sluijs P (2000) Accumulation of rab4GTP in the cytoplasm and association with the peptidyl-prolyl isomerase Pin1 during mitosis. Molecular Biology of the Cell 11: 2201-2211

(3)

(4) Ramelot, TA and Nicholson, LK (2001) Phosphorylation-induced Structural Changes in the Amyloid Precursor Protein Cytoplasmic Tail Detected by NMR. J. Mol. Biol. 307: 871-884

Also referenced on this page:

Zhou XZ, Kops O, Werner A, Lu PJ, Shen M, Stoller G, Kullertz G, Stark M, Fischer G and Lu KP (2000) Pin1-dependent prolyl isomerisation regulates dephosphorylation of Cdc25C and tau proteins. Molecular Cell 6: 873-883

General background on Pin1 references

Pin1 in AD, Apoptosis and Mitotic Events in AD references