**4. Discussion**

**Figure 11.** Alteration of Golgi apparatus of a neuron of the SCN nucleus of the hypothalamus of a case of AD. Electron

. Based on measurements of 100 neurons of SCN (P < 0.005). AD,

AD brains demonstrated serious changes such as disorientation, fragmentation and globular deformation. Mitochondrial alteration was also a frequent phenomenon in numerous astro-

In a substantial number of neurons of the suprachiasmatic and paraventricular nuclei of the hypothalamus the Golgi apparatus appeared to be fragmented and atrophic (**Figure 11**). It was noticed that the atrophy or the fragmentation of Golgi apparatus (**Figure 12**) and the mitochondrial alterations coexisted with dendritic and spinal pathology in the majority of neurons.

micrograph, magnification 124,000×.

**Figure 12.** The volume of Golgi apparatus in nm3

Alzheimer's disease; NC: normal control, SCN, suprachiasmatic nucleus.

cytes and pericytes in AD brains.

178 Cognitive Disorders

Hypothalamus is a crucial brain region for the regulation of substantial homeostatic functions, including the circadian rhythms and the sleep–wake cycle. In Alzheimer's disease and other neurodegenerative disorders [76–78] several hypothalamic nuclei are affected. It seems that the hypothalamic nuclei are not involved simultaneously at the early stages of AD. The suprachiasmatic nucleus seems to be more seriously affected than the others in aging [76]. In previous studies, it was clearly revealed that the total cell population in the suprachiasmatic nucleus is substantially decreased in aging and dramatically in AD [78] in which the hypothalamic dysfunction is closely related to sleep disturbances [79].

The hypothalamic nuclei seem to be involved with various severities in the neurodegenerative process, which progressively results in AD. In addition, the correlation of the alterations of the neuronal dendrites in the hypothalamic nuclei with those seen in the neocortex and the cerebellum, results in concluding that the hypothalamic alterations are modest in comparison with those, which are established in the acoustic area of the cortex, the visual cortex, the prefrontal areas and the cerebellar cortex [80–83].

The fact that the hypothalamus is the essential subcortical center of the homeostatic and autonomic processes, may explain the reason why some nuclei such as the supraoptic and the periventricular ones reserve substantial synaptic density, even in the advanced stages of AD, in correlation with other subcortical and neocortical neurons,.

However, the suprachiasmatic nucleus demonstrated more severe dendritic alterations and synaptic loss than the supraoptic and paraventricular nuclei, a fact which might explain the phenomenon of desynchronization of circadian rhythms in the majority of the patients, who suffer from AD [84] or cognitive decline [85] in the spectrum of other degenerative conditions of the brain [86], given that suprachiasmatic nucleus is of crucial importance for the generation and synchronization of circadian rhythms in man [86, 87]. It is reported that changes of the circadian rhythm (CR), arterial blood pressure and circadian temperature may occur in AD patients [88], especially during the night time [89–91]. Changes also of the melatonin levels are not an unusual phenomenon in advanced senility and AD [92–94]. Sundown syndrome on the other hand, frequently associated with increased motor activity is a rather common condition in advanced AD cases [95].

In a large number of neurons of the hypothalamic nuclei mitochondrial alterations were seen mostly in the soma and the dendrites. Mitochondria play an essential role in the energy supply of the cell, which is crucial in the alteration of reduction-oxidation potential of the cell, in the formation of free radicals, in scavenging activity, as well as in the intracellular calcium control and the activation of apoptotic cascade [96–98]. Normally the mitochondria are numerous in the dendritic profiles and the axons, which have a continuous increased activity during the neuronal interactions. Mitochondrial density is also substantially high in the synaptic components, since mitochondria are the main energy generators for the ceaseless activity of the synapses.

Mitochondrial dysfunction may play an important role for enhancing the neurotoxicity of the Aβ peptide, though increased mitochondrial proteostasis may reduce amyloid-β proteotoxicity [99, 100]. In addition, impaired mitochondrial biogenesis contributes to mitochondrial dysfunction [101], which is directly associated with the oxidative stress, the main activator of the pathogenic cascade of AD [101–103].

In conclusion, the serious autonomic dysfunction in advanced stages of AD composes the tragic epilogue of the disease which is related with the involvement of the hypothalamus dur-

1 1st Department of Neurology, Laboratory of Neuropathology and Electron Microscopy,

[1] Alzheimer A. Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrife

[2] Blessed G, Tomlinson BE, Roth M. The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. British

[3] Reitz C, Mayeux R. Alzheimer disease: Epidemiology, diagnostic criteria, risk factors

[4] Farias ST, Mungas D, Reed BR, Harvey D, DeCarli C. Progression of mild cognitive impairment to dementia in clinic- vs community-based cohorts. Archives of Neurology.

[5] Alzheimer's Association. 2010 Alzheimer's disease facts and figures. Alzheimer's &

[6] El Gaamouch FP, Jing P, Xia J, Cai D. Alzheimer's disease risk genes and lipid regulators.

[7] Scheltens P, Blennow K, Breteler MM, et al. Alzheimer's disease. Lancet. 2016;**388**

[8] van Rossuma IA, Vissera PJ, Knolb DL, van der Fliera WM, Teunissenc CE, Barkhofd F, Blankensteinc MA, Scheltense P. Injury markers but not amyloid markers are associated with rapid progression from mild cognitive impairment to dementia in Alzheimer's dis-

, Demetrios Mitilineos1

The Hypothalamus in Alzheimer's Disease: A Golgi and Electron and Microscope Study

,

http://dx.doi.org/10.5772/intechopen.75887

181

ing the continuous pathological process of the disease.

Stavros Ioannou Baloyannis1,2\*, Ioannis Mavroudis1

\*Address all correspondence to: sibh844@otenet.gr

für Psychiatrie. 1907;**64**:146-148

Dementia. 2010;**6**:158-194

(10043):505-517

Journal of Psychology. 1968;**114**:797-811

and Vasiliki G. Costa1,2

2 Institute for Research on Alzheimer's disease, Iraklion, Lagada, Greece

and biomarkers. Biochemical Pharmacology. 2014;**88**:640-651

2009;**66**:1151-1171. DOI: 10.1001/archneurol.2009.106

ease. Journal of Alzheimer's Disease. 2012;**29**:319-327

Journal of Alzheimer's Disease. 2016;**53**:15-29

Aristotelian University of Thessaloniki, Thessaloniki, Greece

**Author details**

Ioannis S. Baloyannis1

**References**

Mitochondrial motility and accumulation are related to the functional state of the neuron, since mitochondria are transported to regions where necessity for energy is particularly high, as it occurs in the dendritic and axonal profiles and the synapses [103–105]. The shape and size of mitochondria are not stable, since they undergo continual fission and fusion which are necessary for cell survival and harmonious adaptation to changing conditions. Recent studies reported increased mitochondrial fission and decreased fusion, due to increased Aβ peptide interaction with the mitochondrial fission protein Drp 1, inducing increased mitochondrial fragmentation, impaired axonal transport of mitochondria and synaptic degeneration in AD [106, 107]. The consequence of the dynamic fusion and fission processes is the eventual mitophagy of the damaged mitochondria.

Nevertheless, a considerable diminution of the mitochondria is also seen in aging-related neurodegeneration [97, 98], as well as in the early stages of AD, when the mental decline is subtly detected [107]. In normal brains, few spines only contain small round mitochondria in contrast to dendritic branches which mostly include large mitochondria that become numerous during synaptogenesis and in various conditions of hormonal disequilibrium [104, 106]. In AD, marked morphological changes of the mitochondria have been observed in neurons, which show an extensive loss of dendritic spines, associated with giant spines, distortion of spines and synaptic loss. The association of mitochondrial pathology with the synaptic loss is reasonably attributed to a sharp decrease of energy supply by the defected mitochondria [106, 108], a fact which occurs even at the initial stages of AD, when the typical Alzheimer pathology, consisted of the neuritic plaques and the neurofibrillary tangles is still minimal [109, 110].

The mitochondrial pathology, which is observed in the neurons of the hypothalamic nuclei are additional evidences of the causative role that mitochondrial dysfunction play in synaptic degeneration and loss of dendritic arbores in AD [111, 112]. In the suprachiasmatic nucleus of the hypothalamus a substantial number of neurons made evident the marked decrease of the spine density at the secondary and tertiary dendritic branches, which affects reasonably the neuronal interactions in AD. A substantial body of evidence plead also in favor of the important role that mitochondria and Golgi complex play in the morphological and the quantitative stability of the dendritic spines in neuronal networks [105, 109–112], whereas experimental studies underline the spinal vulnerability to nonfibrillar Aβ peptide [110].

The hypothalamus play a central role in autonomic functions, including the generation and control of the circadian rhythms, the thermoregulation, the homeostasis of proteins [25], the maintenance of energy supply and the feeding behavior [113–115]. The pathological alterations of hypothalamic nuclei in AD would induce the autonomic instability, which would be particularly prominent at the advanced stages of the disease, aggravating the clinical condition of the patients exceedingly [116–118], a fact which is also observed in experimental models of AD [119] as well as in the behavioral variant of frontotemporal dementia [120].

In conclusion, the serious autonomic dysfunction in advanced stages of AD composes the tragic epilogue of the disease which is related with the involvement of the hypothalamus during the continuous pathological process of the disease.
