Alzheimer's disease (AD) and prion diseases such as sporadic Creutzfeldt-Jakob disease (sCJD) share common features concerning their molecular pathogenesis and neuropathological presentation and the coexistence of AD and CJD in patients suggest an association between the deposition of the proteolytically processed form of the amyloid precursor protein, beta-amyloid (Abeta), which deposits in AD, and the abnormal form of the prion protein, PrP(Sc), which deposits in sCJD.
Prion protein (PrP) has been localized to amyloid-beta (Abeta) senile plaques in aging and Alzheimer disease, but it is unknown whether PrP is directly involved in plaque formation or represents a reaction to amyloid deposition.
ADAM10, a disintegrin and metalloprotease that plays a key role in the pathogenesis of Alzheimer's disease, was recently shown to use PrP(c) as a substrate.
Although it remains elusive how protein aggregation leads to AD, it is becoming clear that cellular prion protein (PrP<sup>C</sup>) plays an important role in AD pathogenesis.
Although these findings do not entirely exclude a role for PrP in AD or ALS, they do not support the codon 129 genotype as a risk factor for either disease.
Amyloidogenic protein accumulation often occurs in the brain tissues, e.g. in Alzheimer's disease with the deposition of amyloid-beta and Tau, in scrapie and bovine spongiform encephalopathy with the accumulation of prion protein, in Parkinson's disease with the deposition of alpha-synuclein.
An in situ labeling using biotinylated Tat 48-57 peptide was employed in the brain tissue with amyloid deposits made up of Aβ (patients with AD and transgenic AD mice), of prion protein (patients with Gerstmann-Straussler-Scheinker disease), and other amyloidosis, processed by different fixations and pretreatments of histological sections.
Aβo exists in several populations, where prion protein (PrP(C))-interacting Aβo is a high molecular weight Aβ assembly present in multiple mice and humans with AD.
By Western blotting, we found that PrP(C) overexpression down-regulated tau protein and Aβ oligomer binding alleviated the tau reduction induced by wild type but not M128VPrP(C), the high AD risk polymorphic allele in human prion gene.
Cellular prion protein (PrP<sup>C</sup>) binds the scrapie conformation of PrP (PrP<sup>Sc</sup>) and oligomeric β-amyloid peptide (Aβo) to mediate transmissible spongiform encephalopathy (TSE) and Alzheimer's disease (AD), respectively.
CJD is marked primarily by the buildup of misfolded prion protein (PrP(Sc)) in brain, whereas the accrual of beta-amyloid protein (Abeta) and tau protein are characteristic for AD.
Furthermore, there is a possible interrelationship between Alzheimer's disease and prion disease through loss-of-function of PrPC, which leads to the production of amyloid beta.
Fyn is an attractive target for AD therapeutics, not only based on its activation by Aβ via cellular prion protein but also due to its known interaction with tau, uniquely linking the two key pathologies in AD.
Here we investigate the capability of protein 14-3-3, total-tau (t-tau), threonin-181-phosphorylated tau (p-tau), and neuron-specific enolase (NSE) in cerebrospinal fluid (CSF) together with the prion protein gene genotype to discriminate patients with sCJD (n=21) from neurological controls (n=164) and Alzheimer's disease (AD) patients (n=49).
Here, we report a new pathogenic missense mutation (c.[643A>G], p.[I215V]) in the PRNP gene associated with three pathologically confirmed cases: two of Creutzfeldt-Jakob disease (CJD) and one of Alzheimer's disease (AD) in two different families from the same geographical region in Spain.