**5. Conclusions**

*Redirecting Alzheimer Strategy - Tracing Memory Loss to Self Pathology*

dendrites and synaptic terminals via anterograde transport [129].

ER-mitochondrial coupling [133].

ity to oxygenic free radicals [139].

and profound dementia ultimately.

of Alzheimer's disease [22, 148].

In addition, mitochondrial morphology is sometimes controlled by the cytoskeleton, namely the neurofilaments and the microtubules [128]. The change of the shape of the mitochondria occurs mostly during their course through axons,

Many proteins are also important for the mitochondrial morphological integrity and for binding to the cytoskeletal components [130]. Porin is a protein in the outer membrane of the mitochondria that forms voltage-dependent anionic channels, between the mitochondrial inter membrane space and the cytosol [131]. Porin may play crucial role in binding to cytoskeleton [132], because porin-rich domains mostly contain binding sites for MAP2. In addition, recent evidence suggest that amyloid β increases the contact points between endoplasmic reticulum and mitochondria, a phenomenon that occurs in cellular stress, which usually increases

Normally, approximately one-third of the mitochondria are in motion along with microtubules and actin filaments [128, 134], transported to regions where energy requirement is particularly high. The number of the mitochondria is

adjusted, according to the requirement of energy by the cell. It is reasonable that the dysfunctional mitochondria may undergo mitophagy [135], a fact which is associated with neurodegeneration [136] and many devastating conditions of the brain. Morphometric studies of the mitochondria in non-nerve cells in AD revealed a significant reduction in mitochondrial density in endothelial cells [137] as well as in fibroblasts and other cells obtained from patients with AD [138]. Mitochondria from fibroblasts grown in tissue culture from skin samples taken during autopsy of patients of AD, took significantly less calcium than did mitochondria of fibroblasts from age matched normal controls, suggesting that Alzheimer's fibroblast mitochondria have impaired calcium transport processes and showed increased sensitiv-

The most dramatic morphological alterations of the mitochondria are seen in dendritic profiles and the synaptic terminals. The defective mitochondria in AD neurons may not supply adequate levels of adenosine triphosphate (ATP), which is very important factor at the synaptic level for normal neural communication. The low levels of cellular ATP at nerve terminals may lead to the loss of synapses and considerable decline of synaptic function, causing serious cognitive impairment

Mitochondrial alterations in AD are observed also in astrocytes, although mitochondrial dynamics of astrocytes are not yet extensively studied. Astrocytes participate in the degradation of neuronal mitochondria via the process of transmitophagy [140] that occurs following internalization of axonal mitochondria by astrocytic processes, which normally contain very small mitochondria [141]. Astrocytic alterations have been described in cases of familial Alzheimer's disease [142] as well as in advanced cased of sporadic type of Alzheimer's disease [143], demonstrating evidence of the toxicity of the Aβ peptide [144]. The mitochondrial alterations of the astrocytes in early case of Alzheimer's disease enhance the noxious role of the Aβ peptide on the function and the integrity of the astrocytes [145] with serious implications on neuroprotection [146] due to the increased excitotoxicity, which would be a reasonable consequence of the disruption of glutamate/GABA-glutamine

In all of the cases, it was noticed that the morphological alterations of mitochondria in neurons and astrocytes are frequently associated with the fragmentation of Golgi apparatus and the decrease of the vesicles in cis- and trans-Golgi network [19, 56]. The morphological alterations of the mitochondria and the fragmentation of Golgi complex coincide with the dendritic and synaptic pathology in early cases

**48**

cycle [147].

The study in electron microscopy of various areas of the cerebral cortex, including the prefrontal area, the superior parietal lobe, the occipital pole, the visual cortex and the Hessl gyri of the temporal neocortex, and various areas of the cerebellar cortex, the hypothalamus, the mammillary bodies and the medial geniculate body in early cases of Alzheimer's disease, revealed serious morphological alterations of the mitochondria in the perikaryon, the dendritic branches the axons and the synapses.

The most dramatic alteration of the mitochondrial morphology was observed in the dendritic profiles, the dendritic spines and the synapses, associated with poverty of synaptic vesicles and accumulation of multi vesicular bodies.

The morphological alterations of the mitochondria were not dependent on the typical Alzheimer's pathology, since they were seen in areas with minimal β amyloid aggregations and no neurofibrillary tangles, such as the cerebellum, the hypothalamus and the visual cortex, suggesting that the mitochondrial alterations are not the direct consequence of amyloid toxicity.

Mitochondrial alterations were also seen in astrocytes and oligodendrocytes frequently in association with dilatation of the cisternae of the smooth endoplasmic reticulum and Golgi complex.

The mitochondria alterations induce a substantial decline of energy supply to neuronal processes, affecting the protein trafficking, the membrane dynamics as well as the synaptic activity, resulting in gradual synaptic and dendritic degeneration and in neuronal apoptosis eventually.

Mitochondria are strategic points in the pathogenetic field of Alzheimer's disease. New therapeutic strategies aiming at protecting the mitochondria, increasing the energy supply and preventing oxidative stress and calcium imbalance, might be beneficial in the treatment of early cases of AD.
