Dendritic pathology in Alzheimer's disease

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Abstract

Dendritic pathology and decrease of dendritic spine density are prominent phenomena in early cases of Alzheimer's disease, which correlate significantly with the progressive decline of the mental faculties. In previous studies we have described the pathological alterations of the dendrites and the dendritic spines in the prefrontal area of the cortex and the cerebellum. In this study we attempted to describe the morphological alterations of the dendrites and the dendritic spines, quantifying them in the acoustic and the visual cortices of eleven cases of Alzheimer's disease, applying Golgi staining and electron microscopy. In addition, describing also the ultrastructural changes of the mitochondria in the dendritic profiles and the dendritic spines we noticed that mitochondrial pathology correlates substantially with the dystrophic dendrites, the loss of dendritic branches and the pathological alteration of the dendritic spines. We would hypothesize that mitochondrial alterations may play a very important role in dendritic degeneration and the loss of dendritic spines and we should have thought that therapeutic strategies protecting the mitochondria may be beneficial in Alzheimer's disease.

Introduction

Alzheimer's disease is the most common age dependent progressive dementia, involving a number of cellular and biochemical mechanisms resulting in synaptic alterations [1], [2], neurofibrillary degeneration, extracellular deposits of α β peptide and selective neuronal loss.

From the neuropathological point of view neurofibrillary tangles (NFT) and extracellular amyloid accumulations defined as neuritic plaques (NP) are the main hallmarks of the disease [3], [4].

Synaptic alterations, which are prominent even in the early stages of Alzheimer's disease, may play a very important role in the gradual decline of the higher mental faculties, since they correlate better with cognitive impairment than tau pathology, neuronal loss and neuritic plaques [5].

In two independent studies it has been estimated that the correlation between synaptic density and cognitive status is approximately 0.7 [5], [6]. Synaptic alterations are associated with dendritic pathology, which has been noticed long ago, since dystrophic dendrites have been described as a frequent finding in Alzheimer's disease already in the late sixties [7].

The cause of Alzheimer's disease remains enigmatic, in spite of the continuously ongoing research on the field. There is, however, a substantial body of increasing evidence, which pleads in favor of the possible implication of mitochondrial dysfunction in the pathogenesis of late-onset neurodegenerative disorders, including Alzheimer's disease [8], [9], [10], [11].

Mitochondria are vital organelles, for the controlling of cell's homeostasis and viability, by virtue of providing most of the energy for the cellular processes. It is important that mitochondria play a critical role in maintaining cellular calcium homeostasis and cellular signaling cascades for both apoptotic and necrotic cell death pathways [12], [13], [14].

The proper intracellular distribution of mitochondria is adapted to cellular physiology. High concentration of mitochondria occurs, therefore, in subcellular regions with high metabolic requirements, such as in the vicinity of active growth cones of developing neurons [15]. Normally, the number of mitochondria in dendrites correlates with synapse development and may play an important role in the morphogenesis of the spines and the synaptic plasticity [16].

In the present study, we attempted to proceed in morphological and morphometric estimation of dendritic pathology in Alzheimer's disease, correlating also the morphological alterations of the dendritic spines with the mitochondrial alterations.

Section snippets

Materials and methods

Brain tissue was obtained at autopsy from eleven cases, five men and six women, aged 55–84 years, who fulfilled the clinical, neuropsychological and laboratory diagnostic criteria of Alzheimer's disease. All the patients have had a definite history of dementia, which lasted three to seven years. The mean education of the patients was 15.5 years and all of them have spoken the native language fluently.

Screening procedures included medical history, medical examination, cardiological

Light microscope: Golgi impregnation technique

The neuropathological study of the brains of patients who suffered from Alzheimer's disease, verified the clinical diagnosis, since in addition to neuronal loss, Bodian [17], [19] and Gallyas methods [18], [19] visualized neuritic plaques and neurofibrillary tangles, which are the morphological hallmarks of Alzheimer's pathology.

In Golgi and Golgi–Nissl silver impregnation techniques it was revealed that the majority of the neurons in the visual and the acoustic cortices demonstrated a marked

Discussion

Golgi silver impregnation technique is one of the most efficient methods for the visualization of the dendritic arborization of neurons, in order to analyze dendritic parameters, allowing a three dimensional imaging of the entire dendritic field of the impregnated neurons [18], [20]. Using Golgi technique, in spite of the many technical delicate aspects, concerning the number of visualized neurons, we could proceed to an accurate morphometric estimation of the dendritic branches and the

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