Decreased Vasopressin Gene Expression in the Biological Clock of Alzheimer Disease Patients With and Without Depression

Abstract

Circadian rhythm disturbances are frequently present in Alzheimer disease (AD). In the present study, we investigated the expression of vasopressin (AVP) mRNA in the human suprachiasmatic nucleus (SCN). The in situ hybridization procedure on formalin-fixed paraffin-embedded material was improved to such a degree that we could, for the first time, visualize AVP mRNA expressing neurons in the human SCN and carry out quantitative measurements. The total amount of AVP mRNA expressed as masked silver grains in the SCN was 3 times lower in AD patients (n = 14; 2,135 +/- 597 microm2) than in age- and time-of-death-matched controls (n = 11; 6,667 +/- 1466 microm2) (p = 0.003). No significant difference was found in the amount of AVP mRNA between AD patients with depression (n = 7) and without depression (n = 7) (2,985 +/-1103 microm2 and 1,285 +/- 298 microm2, respectively; p = 0.38). In addition, the human SCN AVP mRNA expressing neurons showed a marked day-night difference in controls under 80 years of age. The amount of AVP mRNA was more than 3 times higher during the daytime (9,028 +/- 1709 microm2, n = 7) than at night (2,536 +/- 740 microm2, n = 4; p = 0.02), whereas no clear diurnal rhythm of AVP mRNA in the SCN was observed in AD patients. There was no relationship between the amount of AVP mRNA in the SCN and age at onset of dementia, duration of AD and the neuropathological changes in the cerebral cortex. These findings suggest that the neurobiological basis of the circadian rhythm disturbances that are responsible for behavioral rhythm disorders is located in the SCN. It also explains the beneficial effects of light therapy on nightly restlessness in AD patients.

The Circadian System in Alzheimer’s Disease: Disturbances, Mechanisms, and Opportunities

“…Overall SCN volume has been reported to decrease in dementia of the Alzheimer's type (36), and the expression of the neuropeptide vasoactive intestinal polypeptide (VIP) was found to be decreased in the presenile male SCN (37). There is also a loss of rhythmicity of SCN arginine vasopressin (AVP) during aging (38), and in AD this loss of AVP neurons and rhythmicity is accelerated (39,40). Loss of neurotensin-expressing neurons in the SCN of AD patients is also reported along with increased astrocytes (35).…”

“…Because VIP, AVP, and neurotensin are known to alter SCN neuronal function (41,42), their loss during AD might be of particular functional consequence. Interestingly, there is evidence to suggest that neuropeptide alterations in the SCN occur at early stages of AD and might preface cognitive decline (43). Harper et al (44) also provide evidence that neuropathological progression (as measured by Braak stage) in postmortem AD brains is associated with the severity of circadian abnormalities, suggesting that the circadian rhythm disturbances in AD are directly linked to the central neuropathology of the disease.…”

Mifepristone Repairs Region-Dependent Alteration of Synapsin I in Hippocampus in Rat Model of Depression

“…The layers analyzed in the various hippocampal subfields included stratum pyramidal (SP) and stratum lucidum (SL) in the CA3. The main principle and the procedure of the measurements have been extensively described before (Liu et al, 2000;Hu et al, 2002Hu et al, , 2003. Briefly, each subfield of the hippocampus was manually outlined at low magnification ( Â 4 objective).…”

Contributions of impaired hippocampal plasticity and neurodegeneration to age-related deficits in hormonal pulsatility

“…Inasmuch as the hippocampus is a major site of neurodegenerative pathology in Alzheimer's disease (Mattson, 2004;Mattson and Magnus, 2006), it is reasonable to consider that the damage to this brain region contributes to the perturbed regulation of neuroendocrine systems in this disease. Examples of hormones that are normally released in a pulsatile manner, but are released in a dysregulated manner in Alzheimer's disease include cortisol (Ferrari et al, 2001), vasopressin (Liu et al, 2000) and melatonin (Skene and Swaab, 2003). When taken together with the data from animal studies described below, the correlation of hippocampal pathology with dysregulated neuroendocrine pulsatility in Alzheimer's disease is consistent with a prominent role for the hippocampus in control of neuroendocrine rhythms.…”