Alzheimer's Disease and Frontotemporal Dementias

AD Tangle	FTD Tangle	PiD Pick Body	CBD Tangle 1

CBD Tangle 2	Isolated Tau Filaments	NIFID: Nuclear Inclusions	NIFID: Cytoplasmic Inclusions

GFAP Immunolabelling

Elucidation of Endogenous Pin1 Distribution and Shortfalls in Frontotemporal Dementias (FTDs):

We have developed a novel TEM methodology whereby the PPIase protein Pin1 is used as a probe for its target proteins within tissues (Thorpe et al., 1999 ). See more detail on the methodology of using chaperone proteins as 'TEM Probes ' of their target proteins.

Previously, we have utilised this latter methodology in work including a preliminary examination (restricted to one brain sample) of the levels and distribution of both endogenous Pin1 and exogenous Pin1 binding in (normal and) AD human brain (Thorpe et al., 2001). This work showed enhanced levels of Pin1 binding to its (unbound, phosphorylated) target proteins in AD (compared with normal) brain. In AD-affected neurones, immunolabelling for endogenous Pin1 showed a redirection to the cytoplasm (compared with normal neurons, while the highest levels of (exogenous) Pin1 binding were to the tau-immunoreactive tangles , reflecting the large amounts of phosphorylated tau and indicative of a shortfall of available Pin1 in these cells.

Recently, we have extended this work to examine a range of FTDs

(See: 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 )

We found that similar Pin1 redistribution and shortfalls occur in neurons affected by FTDs characterized by abnormal protein aggregates of tau and other cytoskeletal proteins.

Endogenous Pin1 Distribution

Shortfalls of Pin1 revealed by Exogenous Rec-Pin1 Binding

We suggested that, as nuclear Pin1 depletion causes apoptosis, shortfalls in regard to both nuclear and p-tau targets may contribute to neuronal dysfunction.

Therefore, this might be a unifying, contributory factor towards neuronal death in these dementias.

Ultrastructural and Immunological Investigations of Neuronal Intermediate Filament Inclusion Disease (NIFID)

(See: Mosaheb S, Thorpe JR, Hashemzadeh-Bonehi L,Bigio EH,Gearing M, Cairns NJ (2005) Neuronal intranuclear inclusions are ultrastructurally and immunologically distinct from cytoplasmic inclusions of neuronal intermediate filament inclusion disease (NIFID). Acta Neuropathologica 110: 360-368 )

An Example of an Intranuclear Inclusion (INI) in NIFID:

( * = INI ; bar = 1mm)

Enlarged View of Boxed Area in Image Above:

(bar = 0.5mm)

High Mag Image of INI Filaments:

(bar = 100nm)

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Cytoplasmic Inclusions:

Portion of the inclusion immunolabelled for a-internexin

A Novel Association of Pin1 with Lipofuscin

Hashemzadeh-Bonehi L, Phillips RG, Cairns NJ, Mosaheb S, Thorpe JR (2006) Pin1 protein associates with neuronal lipofuscin: potential consequences in age-related neurodegeneration. Experimental Neurology 199: 328-338

In ageing normal neurons we have observed a novel association of Pin1 protein with lipofuscin (Hashemzadeh-Bonehi et al., Experimental Neurology In Press); the highest levels of endogenous neuronal Pin1 protein were seen to associate with granules of this age-related pigment. On the basis of the evidence of our data, we hypothesised that this association might result from oxidative stress effects upon the protein with ageing and/or neurodegeneration and its resultant clearance through the endo-/lysosomal pathway; this latter could account for our observed deficits of the protein. Interestingly, the apparent time-of-onset of our observed neuronal Pin1 shortfalls equates to late middle age, when both lipofuscin accumulations become significant and susceptibility to late-onset neurodegenerative diseases occurs.

We suggested that our data were consistent with the possibility that neuronal Pin1 deficits may be a contributory factor in neurodegeneration associated with ageing.

Very notably, in regard to this latter point, it has recently been shown that Pin1 is oxidatively modified in MCI hippocampus, and the authors concluded that the oxidative inactivation of Pin1 could be involved in the progression from MCI to AD (Butterfield et al., In Press)