Morphometric alterations of Golgi apparatus in Alzheimer's disease are related to tau hyperphosphorylation

Abstract

The Golgi apparatus (GA) is a highly dynamic organelle, which is mainly involved in the post-translational processing and targeting of cellular proteins and which undergoes significant morphological changes in response to different physiological and pathological conditions. In the present study, we have analyzed the possible alterations of GA in neurons from the temporal neocortex and hippocampus of Alzheimer's disease (AD) patients, using double immunofluorescence techniques, confocal microscopy and 3D quantification techniques. We found that in AD patients, the percentage of temporal neocortical and CA1 hippocampal pyramidal neurons with a highly altered GA is much higher (approximately 65%) in neurons with neurofibrillary tangles (NFT) than in NFT-free neurons (approximately 6%). Quantitative analysis of the surface area and volume of GA elements in neurons revealed that, compared with NFT-free neurons, NFT-bearing neurons had a reduction of approximately one half in neocortical neurons and one third in CA1 neurons. In both regions, neurons with a pre-tangle stage of phospho-tau accumulation had surface area and GA volume values that were intermediate, that is, between those of NFT-free and NFT-bearing neurons. These findings support the idea that the progressive accumulation of phospho-tau is associated with structural alterations of the GA including fragmentation and a decrease in the surface area and volume of GA elements. These alterations likely impact the processing and trafficking of proteins, which might contribute to neuronal dysfunction in AD.

The Neuroanatomy of the Reticular Nucleus Locus Coeruleus in Alzheimer’s Disease

“…A recent study demonstrates an accumulation of P-Tau pyramidal cell bodies from AD patients correlates with alterations of the Golgi apparatus (Antón-Fernández et al, 2017 ).…”

Phospho-Tau Accumulation and Structural Alterations of the Golgi Apparatus of Cortical Pyramidal Neurons in the P301S Tauopathy Mouse Model

“…However, it should be noted that, in our material, we did not find evidence for GA fragmentation in AT8+ neurons, which contrasts with the fragmentation reported in CP-13+ spinal cord motor neurons (in which tau phosphorylated at serine 202 is labeled), in a study using 10–12-month-old JNPL3 mutant mice, which overexpress P301L mutated tau gene [ 16 ]. Several factors might have contributed the differences between the two studies regarding the fragmentation of the GA, namely differences in 1) the age of the animals studied [ 19 ]; 2) the type of tau mutation and the consequent type of hyperphosphorylation and aggregation; 3) the antibodies used to detect phospho-tau; and 4) the neuronal population studied. The present observations also contrast with the fragmentation of the GA described in AT8+ cortical pyramidal cells from AD patients [ 19 ], indicating that GA alterations in P301 mouse only partially reproduce those occurring during the development of the disease.…”

“…Fiji software (3D object counter tool) was used to analyze the volume and surface area of the elements immunostained for the different GA markers in image stacks. Based on methods used in previous studies (see [ 19 ] for a detailed description), we cropped 3D substacks from the original confocal stacks taken from AT8-MG160 or AT8-Grasp65 double-stained sections counterstained with DAPI, trying to limit the analysis to the complete GA corresponding to the somata of single neurons. In P301S animals, these cells included pyramidal neurons with (AT8+) or without (AT8 –) hyperphosphorylated tau, which were selected such that they were similar in size and from neighboring zones with similar Z depths within the stacks, in order to minimize possible sources of bias due to neuronal population heterogeneity or antibody penetration within the tissue.…”

“…For example, Salehi et al [ 17 ] reported that there was fragmentation and a decrease in size of the GA and that these alterations were unrelated to the intracellular content of NFT, whereas Stieber et al [ 18 ] reported that these alterations were preferentially associated with neurons devoid of NTF. However, recent studies in the neocortex and hippocampus of AD patients using different experimental approaches to those employed by Stieber et al [ 18 ] and Salehi et al [ 17 ] have shown that the progressive accumulation of hyperphosphorylated tau is associated with the reduction and the morphometric alterations of GA [ 19 ]. Nevertheless, there are factors that might affect the structural characteristics of the GA, such as the age of the patients, tissue fixation procedure, and postmortem period prior to fixation [ 19 ].…”

“…However, recent studies in the neocortex and hippocampus of AD patients using different experimental approaches to those employed by Stieber et al [ 18 ] and Salehi et al [ 17 ] have shown that the progressive accumulation of hyperphosphorylated tau is associated with the reduction and the morphometric alterations of GA [ 19 ]. Nevertheless, there are factors that might affect the structural characteristics of the GA, such as the age of the patients, tissue fixation procedure, and postmortem period prior to fixation [ 19 ]. In addition to NFTs, AD patient tissue is characterized by other pathologic hallmarks, namely, the accumulation of extracellular fibrillar Aβ in amyloid plaques and elevated levels of soluble Aβ oligomers in the brain.…”