Synaptic Alterations in the Vestibulocerebellar System in Alzheimer's Disease - A Golgi and Electron Microscope Study

Abstract

Alzheimer's disease is one of the main causes of cognitive impairment in the presenium and senium. Despite increased efforts in investigations of the aetiological background of the disease, most of the pathogenetic mechanisms remain unclear. From the morphological point of view, neurofibrillary degeneration and neuritic plaques, the main hallmarks of Alzheimer's disease, are mostly seen in the hippocampus and the cortex of the cerebral hemispheres. In contrast, the cerebellum and brain stem demonstrate minimal aggregates of neurofibrillary tangles. In addition, the neuronal population is better preserved in the cerebellum in contrast to the cortex of the brain hemispheres. In this study we attempted to detect alterations to the synapses in the vestibulocerebellar system, which is better preserved than the other structures in the central nervous system, even in the advanced stages of Alzheimer's disease. The morphological analysis is based on examination of 10 brains via electron microscopy and silver impregnation in the nodule, flocculus and vestibular nuclei. Morphological analysis revealed a limited number of neuritic plaques and minimal neurofibrillary tangles. However, synaptic alterations of the mossy fibres, granule cell dendrites, parallel fibres and Purkinje cell dendritic spines were extensively seen in Alzheimer's brains, in contrast to normal controls. In the granule layer, granule and Golgi cells were considerably decreased in number. The synapses between the mossy fibres and the granule cell dendrites were also decreased. Some of the synapses contained a limited number of polymorphous synaptic vesicles, numerous atypical mitochondria and dense bodies. Most synaptic alterations were in the mossy fibres' presynaptic terminals. The number of synaptic contacts between the mossy fibre terminals and the dendrites of the granule and Golgi cells was dramatically decreased. In the vestibular nuclei, substantial loss of synapses among the local neuronal circuits was also observed. Morphological alterations of the Golgi apparatus were seen in several neurons of the medial and lateral vestibular nuclei. In conclusion, these observations obviously plead in favour of a synaptic pathology among the primary pathogenetic processes in Alzheimer's.

Sparse temporally dynamic resting-state functional connectivity networks for early MCI identification

“…Parts of the cerebellum regions of MCI patients underwent structural degenerative (Baloyannis et al, 2000; Fukutani et al, 1997; Li et al, 1994; Sjöbeck and Englund, 2001; Wang et al, 2002), including reduction of Purkinje cell density, atrophy of the molecular and granular cell layer, and concentration of amyloid plaques in the cerebellar cortex (Wegiel et al, 1999). In a study that manually partitioned human cerebellum into four substructures, i.e., anterior, superior posterior, inferior posterior lobes, and corpus medullare on each hemisphere, the posterior cerebellar lobe experience significant volume reduction in AD patients (Thomann et al, 2008), leading to poorer cognitive performance.…”

Early limited nitrosamine exposures exacerbate high fat diet-mediated type 2 diabetes and neurodegeneration

“…We focused our investigations on the cerebellum because the cerebellum can be adversely affected in AD, as well as other neurodegenerative diseases [47,50,53,56,59,60,65,68,69,71], and cerebellar degeneration causes cognitive impairment [49,57-59,62,63,66,67,72]. Previous studies demonstrated significant structural, functional, and metabolic abnormalities in AD cerebella [57-59,82], including insulin and IGF resistance [30], similar to the findings in more traditional targets of AD, i.e.…”

“…Cerebellar degeneration in AD is manifested clinically by gait instability and increased falling [66], and structurally, by significant atrophy of the posterior cerebellar lobes, which correlates with cognitive impairment [67]. The major histopathological features of AD cerebellar atrophy include, reductions in Purkinje cell population, atrophy of the molecular and granule cell layers [68], increased amyloid deposition and gliosis in the cortex [69]; increased ubiquitin-immunoreactivity in senile plaques and degenerating neurites [70]; extensive abnormalities in dendritic spine density and synaptic structure in vestibulocerebellar, visual, and auditory pathways [71,72]; and degeneration of cerebellar white matter fibers with loss of climbing fibers and presynaptic varicosities [73]. In aggregate, synaptic pathology, rather than neurofibrillary tangles and plaques, represents the main correlate of cerebellar degeneration in AD.…”

Mitochondrial Dysfunction and Synaptic Transmission Failure in Alzheimer’s Disease

“…Stepwise, SV cycling includes the loading of neurotransmitters into SVs, the SV trafficking to and docking at the active zone of presynapses, the releasing of neurotransmitters, and at last the endocytosis and recycling of SVs [104]. In addition to synaptic loss, dramatically decreased expression levels of SV proteins and their coding mRNAs have been discerned in vast areas of postmortem AD brains including most part of the neocortex, limbic system, basal ganglia, and cerebellum; and the changes have a strong correlation to cognitive impairment [19, 105–111]. It should be mentioned that the severity of these changes varies; and the relatively AD sensitive brain regions such as hippocampus, frontal, temporal, and parietal lobes, where there are more severe Aβ deposition, tau pathology, and mitochondrial damages, are early affected areas and demonstrate a greater loss of SV proteins and their coding mRNAs [108–111].…”