Neuropathology of Alzheimer’s Disease, as Seen in Fixed Tissues

Summary

The progress of in vivo imaging will in the future determine if deductions made from fixed tissue concerning the pathology of Alzheimer’s disease (AD) were correct. It will mainly enable us to apprehend directly the chronological sequence of the lesions and their duration. This paper reviews some of the data concerning the classical pathology of AD. Lesions may be categorized into Aβ peptide deposition, tau accumulation and loss of neurons and of synapses. Aβ peptide originates from the amyloid precursor protein, a transmembrane protein that is found in lipid rafts of the cellular membrane. Accumulation of flotillin-1, a raft marker, in AD indicates a disturbance of this membrane transport system in AD. Diffuse deposits of Aβ peptide within the cerebral cortex have little clinical consequence. Focal deposits are generally amyloid, i.e., Congo red positive and highly insoluble. They are usually associated with microglial activation and low-grade inflammation. Aβ peptide is initially embedded in a cell membrane and partly hydrophobic. It may actually be linked to cholesterol in the extracellular milieu, as recently suggested. Tau accumulation takes place in the cell body, the dendrites and the axons of the neurons, forming, respectively, neurofibrillary tangles, neuropil threads and coronae of senile plaques. Heiko and Eva Braak have shown that the progression of neurofibrillary pathology takes place in a stereotyped manner that appears to be correlated with the clinical symptoms. Contrary to the prediction of the amyloid cascade hypothesis, neurofibrillary pathology in the rhinal cortex and pyramidal sectors of the hippocampus most often precedes the first morphological evidence of All peptide accumulation. This observation suggests that tau and amyloid pathologies are, at the start, independent processes that secondarily interact. Data from transgenic mice support this view: neurofibrillary pathology is not observed in APP transgenic mice, except if a human mutated tau transgene has also been incorporated. Progression of the lesions is different in the entorhinal-hippocampal region and in the isocortex. In the former, tau pathology may be observed in the absence of Aβ deposition, which appears to be a relatively late phenomenon. In the isocortex, by contrast, Aβ peptide deposition is the first observable event.

The sequence of the lesions in the isocortex appears to be the following: diffuse, focal, then amyloid deposits, neuropil threads, neuritic corona of the plaque and finally neurofibrillary tangles. Neuronal loss, in this sequence of events, occurs probably at a late stage, shortly preceding or occurring at the same time as tangle formation. Synaptic loss is a more complex process than previously thought: vesicular markers of the synapse drop sharply in advanced cases, whereas membrane markers are relatively spared. The decrease in the number of synapses is associated with enlargement of the ones that survive.

Up to now, observation of fixed brain tissue has dealt almost exclusively with proteins immobilized by formalin or other fixatives. Recent data show that membrane lipids play an essential role in the pathogenesis of AD. One of the future challenges of neuropathology will be to visualize not only the proteins but also the membrane domains that bear them.