No abstract

Cholesterol is required for the formation and function of some signalling platforms. In synaptosomes, amyloid-β (Aβ) oligomers, the causative agent in Alzheimer's disease, bind to cellular prion proteins (PrP) resulting in increased cholesterol concentrations, translocation of cytoplasmic phospholipase A (cPLA, also known as PLA2G4A) to lipid rafts, and activation of cPLA The formation of Aβ-PrP complexes is controlled by the cholesterol ester cycle. In this study, Aβ activated cholesterol ester hydrolases, which released cholesterol from stores of cholesterol esters and stabilised Aβ-PrP complexes, resulting in activated cPLA Conversely, cholesterol esterification reduced cholesterol concentrations causing the dispersal of Aβ-PrP complexes. In cultured neurons, the cholesterol ester cycle regulated Aβ-induced synapse damage; cholesterol ester hydrolase inhibitors protected neurons, while inhibition of cholesterol esterification significantly increased Aβ-induced synapse damage. An understanding of the molecular mechanisms involved in the dispersal of signalling complexes is important as failure to deactivate signalling pathways can lead to pathology. This study demonstrates that esterification of cholesterol is a key factor in the dispersal of Aβ-induced signalling platforms involved in the activation of cPLA and synapse degeneration.

Summary Background Trauma to the foot and distal phalanx are common presenting complaints. In contrast, neoplasia of the distal phalanx or hoof region is rarely reported. Within the foot, keratomas are the most frequently reported neoplasm. The gross and radiographic appearance of keratomas is well documented; however, this is less well established for other neoplasms of the hoof capsule. Objective This paper presents four cases which had clinical and radiographic similarities to keratomas; however, key differences were observed. We aimed to highlight the key differences in imaging findings and clinical progression. Study design Retrospective multicentre case series. Methods Cases identified between 2015 and 2019 with pathological diagnoses of neoplasia within the foot at Purdue University Veterinary teaching hospital and Langford Equine Hospital. Clinical records were examined, and physical examination, imaging, surgical and pathological findings are presented. Results The four cases presented had similarities to keratomas; however, key differences were present. Marked lameness was noted in all three cases with aggressive neoplasia, whereas one case was not lame at presentation but still had a diagnosis of a benign neoplasm. Radiographic examination showed significant lucent areas with poor delineation at the margins and suspected invasion into the distal phalanx. For the two melanomas and the squamous cell carcinoma, deterioration was marked and rapid, ultimately leading to euthanasia. The benign neoplasm was managed successfully for 2 years and lost to follow‐up. Conclusions Although rare, neoplasms other than keratoma do occur in the foot. Careful interpretation of the imaging findings, consideration of additional imaging such as vascular studies or cross‐sectional imaging, and submission of tissue for biopsy are strongly recommended if there is any suspicion of the lesion being anything other than a keratoma.

The cellular prion protein (PrP) acts as a scaffold protein that organises signalling complexes. In synaptosomes, the aggregation of PrP by amyloid-β (Aβ) oligomers attracts and activates cytoplasmic phospholipase A (cPLA), leading to synapse degeneration. The signalling platform is dependent on cholesterol released from cholesterol esters by cholesterol ester hydrolases (CEHs). The activation of cPLA requires cholesterol released from cholesterol esters by cholesterol ester hydrolases (CEHs), enzymes dependent upon platelet activating factor (PAF) released by activated cPLA This demonstrates a positive feedback system in which activated cPLA increased cholesterol concentrations, which in turn facilitated cPLA activation. PAF was also required for the incorporation of the tyrosine kinase Fyn and cyclooxygenase (COX)-2 into Aβ-PrP-cPLA complexes. As a failure to deactivate signalling complexes can lead to pathology, the mechanisms involved in their dispersal were studied. PAF facilitated the incorporation of acyl-coenzyme A:cholesterol acyltransferase (ACAT)-1 into Aβ-PrP-cPLA-COX-2-Fyn complexes. The esterification of cholesterol reduced cholesterol concentrations, causing dispersal of Aβ-PrP-cPLA-COX-2-Fyn complexes and the cessation of signalling. This study identifies PAF as a key mediator regulating the cholesterol ester cycle, activation of cPLA and COX-2 within synapses, and synapse damage.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ) and the loss of synapses. Aggregation of the cellular prion protein (PrPC) by Aβ oligomers induced synapse damage in cultured neurons. PrPC is attached to membranes via a glycosylphosphatidylinositol (GPI) anchor, the composition of which affects protein targeting and cell signaling. Monoacylated PrPC incorporated into neurons bound “natural Aβ”, sequestering Aβ outside lipid rafts and preventing its accumulation at synapses. The presence of monoacylated PrPC reduced the Aβ-induced activation of cytoplasmic phospholipase A2 (cPLA2) and Aβ-induced synapse damage. This protective effect was stimulus specific, as treated neurons remained sensitive to α-synuclein, a protein associated with synapse damage in Parkinson’s disease. In synaptosomes, the aggregation of PrPC by Aβ oligomers triggered the formation of a signaling complex containing the cPLA2.a process, disrupted by monoacylated PrPC. We propose that monoacylated PrPC acts as a molecular sponge, binding Aβ oligomers at the neuronal perikarya without activating cPLA2 or triggering synapse damage.