**1. Introduction**

Alzheimer's disease (AD) is a progressive devastating non reversible neurodegenerative disorder of the central nervous system, which has been recognized as the most common cause of serious cognitive decline in elderly people resulting in profound dementia [1, 2] with no effective therapy [3]. It is reasonable that AD induces a huge social burden and has a serious economic impact, since it starts frequently as mild cognitive impairment, resulting eventually in dementia, as the time advances [4, 5], affecting over 26 million people worldwide [6, 7].

Many hypotheses have been submitted concerning the various mechanisms of the pathogenetic process of AD, based mostly on the neuropathological investigation and the experimental models of AD. Moreover the genetic investigation of the familial AD underline the heterogenetic character of AD, though the clinical investigation suggests that the disease at the advanced stages follows a common pathway with many other degenerative conditions of

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

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

169

The oxidative stress correlated with the cortical and subcortical deposits of Aβ peptide can obviously play an important pathogenetic role in AD [39, 40]. In addition, the marked mitochondrial alterations in neurons and glial cells in cortical and subcortical structures and in cerebellum [40, 41], which are mostly observed in dendrites deprived of spines, may contribute in shaping the pathogenetic pattern of the disease. On the other hand electron microscopy in early cases of AD revealed fragmentation of the cisternae of Golgi apparatus [42] even in areas where the characteristic Alzheimer's pathology was unremarkable. The morphological alteration of Golgi complex may be associated with the impairment of protein trafficking, acting as an additional pathogenetic component of AD. It is well recognized that Golgi complex is of instrumental importance in sorting and trafficking of the plasma proteins toward their final

The autonomic nervous system participates in the brain dysfunction in case of AD either in the form of autonomic hyperactivity or of autonomic failure under the influence of strong exterior emotional inputs. The hypothalamus, the principal autonomic center is involved in advanced stages of AD [44–49], whereas the suprachiasmatic nucleus (SCN), which is the main circadian pacemaker, undergoes several continuous alterations during the course of the disease [50]. The activation of the hypothalamic-pituitary-adrenal (HPA) pathway by exterior stimuli, inducing stress increase substantially the glucocorticoid release [49], which may modify the emotional and autonomic reactions of the patients who suffer

The modification of the volume of the third ventricle in AD may be considered as an evidence of the involvement of the hypothalamus, which would undergo pathological alterations in AD [51, 52], that may have a different molecular and cellular character in comparison with those observed in the hippocampus and in the cortex of the brain hemispheres [53], since hypothalamic plaques are not associated with increased gliosis or prominent disruption of the neuropile [53]. In addition the majority of diffuse plaques in the hypothalamus in case of AD may be labeled with an antiserum to the Aβ peptide, of the beta-amyloid precursor proteins (beta APPs), whereas Aβ peptide-immunoreactive plaques are rather uncommon in the hypothalamus of patients without AD [54]. It was also noticed that the neurofibrillary degeneration in the hypothalamus involves primarily those neurons that are associated with

Following our previous study [54] on the morphological alterations of the hypothalamus in AD, in this study we attempted to describe some additional morphological findings, concerning the hypothalamic nuclei and the dendritic and spinal pathology in early cases of

cortical areas which show prominent Alzheimer's pathology [53].

the brain [37, 38].

membranic target [43].

from AD.

Alzheimer's disease.

The pathogenesis of AD involves a considerable number of cellular and molecular underlying mechanisms, as well as many genetic or acquired overlapping risk factors [8], such as diabetes, obesity and psychosocial stress, which although are among the modifiable factors, may contribute substantially in the rapid mental deterioration, aggravating the clinical phenomenology of the disease [9].

A substantial number of clinical observations and laboratory investigations plead in favor of brain injury [8], stress [10–12], or stress-related psychiatric disorders [13, 14], type 2 diabetes [15, 16] insulin resistance [17, 18], inflammation [19] and depression [12, 20] as probable causative factors in the pathogenetic spectrum of AD [21].

The neuropathological profile of AD includes the formation of neuritic plaques, the neurofibrillary degeneration in the form of tangles of highly phosphorylated tau proteins, the dendritic alterations, the spinal pathology, the marked alterations of dendritic spines, the dramatic reduce of the number of synapses, the substantial neuronal loss [22, 23], which is quite prominent mostly in limbic structures and selectively in various areas of the cortex of the brain hemispheres, as well as the phenomena of inflammation [24]. The prolonged gathering of the Aβ peptide in the brain activates microglial cells and pericytes reasonably, inducing neuroinflammation, which participates obviously in the ongoing pathogenic cascade of AD [24]. Coarse aggregations of Aβ amyloid peptide in the brain may consequently promote degenerations of neurons and astrocytes, which are particularly sensitive in changes of protein homeostasis, energy decline and oxidative stress [25]. The vascular factor is an additional component of the pathogenetic cascade of AD, since the disruption of the BBB and the alterations of the brain capillaries [26, 27] could lead to infiltration of the perivascular space by immune cells, promoting reasonably the exacerbation of inflammatory reactions [24].

The initial clinical manifestations of AD are subtle. However, as the time advances progressive memory and learning impairment [28], language disturbances, visuospatial disorientation, ideomotor apraxia, behavioral disturbances, depressive symptoms [29–32], personality changes [33–35], and a multitude of non-cognitive symptoms, such as sleep disruption, circadian dysrhythmia, changes in body weight and autonomic dysfunction progressively establish as principal dominant deficits in AD [36]. Sleep disturbances, on the other hand, might have a negative impact on the amyloid burden and the cognitive capacity of the patients, though the etiopathogenic mechanisms of the sporadic cases of AD remain yet unclear.

Many hypotheses have been submitted concerning the various mechanisms of the pathogenetic process of AD, based mostly on the neuropathological investigation and the experimental models of AD. Moreover the genetic investigation of the familial AD underline the heterogenetic character of AD, though the clinical investigation suggests that the disease at the advanced stages follows a common pathway with many other degenerative conditions of the brain [37, 38].

**1. Introduction**

168 Cognitive Disorders

wide [6, 7].

nomenology of the disease [9].

tory reactions [24].

ative factors in the pathogenetic spectrum of AD [21].

Alzheimer's disease (AD) is a progressive devastating non reversible neurodegenerative disorder of the central nervous system, which has been recognized as the most common cause of serious cognitive decline in elderly people resulting in profound dementia [1, 2] with no effective therapy [3]. It is reasonable that AD induces a huge social burden and has a serious economic impact, since it starts frequently as mild cognitive impairment, resulting eventually in dementia, as the time advances [4, 5], affecting over 26 million people world-

The pathogenesis of AD involves a considerable number of cellular and molecular underlying mechanisms, as well as many genetic or acquired overlapping risk factors [8], such as diabetes, obesity and psychosocial stress, which although are among the modifiable factors, may contribute substantially in the rapid mental deterioration, aggravating the clinical phe-

A substantial number of clinical observations and laboratory investigations plead in favor of brain injury [8], stress [10–12], or stress-related psychiatric disorders [13, 14], type 2 diabetes [15, 16] insulin resistance [17, 18], inflammation [19] and depression [12, 20] as probable caus-

The neuropathological profile of AD includes the formation of neuritic plaques, the neurofibrillary degeneration in the form of tangles of highly phosphorylated tau proteins, the dendritic alterations, the spinal pathology, the marked alterations of dendritic spines, the dramatic reduce of the number of synapses, the substantial neuronal loss [22, 23], which is quite prominent mostly in limbic structures and selectively in various areas of the cortex of the brain hemispheres, as well as the phenomena of inflammation [24]. The prolonged gathering of the Aβ peptide in the brain activates microglial cells and pericytes reasonably, inducing neuroinflammation, which participates obviously in the ongoing pathogenic cascade of AD [24]. Coarse aggregations of Aβ amyloid peptide in the brain may consequently promote degenerations of neurons and astrocytes, which are particularly sensitive in changes of protein homeostasis, energy decline and oxidative stress [25]. The vascular factor is an additional component of the pathogenetic cascade of AD, since the disruption of the BBB and the alterations of the brain capillaries [26, 27] could lead to infiltration of the perivascular space by immune cells, promoting reasonably the exacerbation of inflamma-

The initial clinical manifestations of AD are subtle. However, as the time advances progressive memory and learning impairment [28], language disturbances, visuospatial disorientation, ideomotor apraxia, behavioral disturbances, depressive symptoms [29–32], personality changes [33–35], and a multitude of non-cognitive symptoms, such as sleep disruption, circadian dysrhythmia, changes in body weight and autonomic dysfunction progressively establish as principal dominant deficits in AD [36]. Sleep disturbances, on the other hand, might have a negative impact on the amyloid burden and the cognitive capacity of the patients, though the etiopathogenic mechanisms of the sporadic cases of AD remain yet unclear.

The oxidative stress correlated with the cortical and subcortical deposits of Aβ peptide can obviously play an important pathogenetic role in AD [39, 40]. In addition, the marked mitochondrial alterations in neurons and glial cells in cortical and subcortical structures and in cerebellum [40, 41], which are mostly observed in dendrites deprived of spines, may contribute in shaping the pathogenetic pattern of the disease. On the other hand electron microscopy in early cases of AD revealed fragmentation of the cisternae of Golgi apparatus [42] even in areas where the characteristic Alzheimer's pathology was unremarkable. The morphological alteration of Golgi complex may be associated with the impairment of protein trafficking, acting as an additional pathogenetic component of AD. It is well recognized that Golgi complex is of instrumental importance in sorting and trafficking of the plasma proteins toward their final membranic target [43].

The autonomic nervous system participates in the brain dysfunction in case of AD either in the form of autonomic hyperactivity or of autonomic failure under the influence of strong exterior emotional inputs. The hypothalamus, the principal autonomic center is involved in advanced stages of AD [44–49], whereas the suprachiasmatic nucleus (SCN), which is the main circadian pacemaker, undergoes several continuous alterations during the course of the disease [50]. The activation of the hypothalamic-pituitary-adrenal (HPA) pathway by exterior stimuli, inducing stress increase substantially the glucocorticoid release [49], which may modify the emotional and autonomic reactions of the patients who suffer from AD.

The modification of the volume of the third ventricle in AD may be considered as an evidence of the involvement of the hypothalamus, which would undergo pathological alterations in AD [51, 52], that may have a different molecular and cellular character in comparison with those observed in the hippocampus and in the cortex of the brain hemispheres [53], since hypothalamic plaques are not associated with increased gliosis or prominent disruption of the neuropile [53]. In addition the majority of diffuse plaques in the hypothalamus in case of AD may be labeled with an antiserum to the Aβ peptide, of the beta-amyloid precursor proteins (beta APPs), whereas Aβ peptide-immunoreactive plaques are rather uncommon in the hypothalamus of patients without AD [54]. It was also noticed that the neurofibrillary degeneration in the hypothalamus involves primarily those neurons that are associated with cortical areas which show prominent Alzheimer's pathology [53].

Following our previous study [54] on the morphological alterations of the hypothalamus in AD, in this study we attempted to describe some additional morphological findings, concerning the hypothalamic nuclei and the dendritic and spinal pathology in early cases of Alzheimer's disease.
