The association between low testosterone levels and Alzheimer's d... more The association between low testosterone levels and Alzheimer's disease (AD) amyloid beta-peptide (Abeta) metabolism was investigated in brain and kidney of guinea pigs. The expression of Abeta peptide in the brain and kidney was assessed by using the immunohistochemistry method. No expression of Abeta was seen in both groups of animals. This negative staining was found until the fourth week following castration. The formation of Abeta in guinea pigs is perhaps not a short duration process and may undergo different metabolic pathway compare to humans. castration was not associated with the formation of Abeta in the brain and kidneys during a 1-month period and might require a longer period of time.
The association between low testosterone levels and Alzheimer's disease (AD) amyloid beta-pep... more The association between low testosterone levels and Alzheimer's disease (AD) amyloid beta-peptide (Abeta) metabolism was investigated in brain and kidney of guinea pigs. The expression of Abeta peptide in the brain and kidney was assessed by using the immunohistochemistry method. No expression of Abeta was seen in both groups of animals. This negative staining was found until the fourth week following castration. The formation of Abeta in guinea pigs is perhaps not a short duration process and may undergo different metabolic pathway compare to humans. castration was not associated with the formation of Abeta in the brain and kidneys during a 1-month period and might require a longer period of time.
CNS & neurological disorders drug targets, Jan 10, 2015
Reduction in testosterone levels in men during aging is associated with cognitive decline and ris... more Reduction in testosterone levels in men during aging is associated with cognitive decline and risk of dementia. Animal studies have shown benefits for testosterone supplementation in improving cognition and reducing Alzheimer's disease pathology. In a randomized, placebo-controlled, crossover study of men with subjective memory complaint and low testosterone levels, we investigated whether testosterone treatment significantly improved performance on various measures of cognitive functioning. Forty-four men were administered a battery of neuropsychological tests to establish the baseline prior to being randomly divided into two groups. The first group (Group A) received 24 weeks of testosterone treatment (T treatment) followed by 4 weeks washout, and then 24 weeks of placebo (P); the second group (Group B) received the same treatments, in reverse order (Placebo, washout, and then T treatment). In group A (TP), compared to baseline, there was a modest (1 point) but significant im...
Hormonal changes associated with ageing have been implicated in the pathogenesis of Alzheimer'... more Hormonal changes associated with ageing have been implicated in the pathogenesis of Alzheimer's disease (AD), the most common form of dementia. Reductions in serum testosterone and increases in luteinizing hormone (LH) are established AD risk factors for dementia in men and have important roles in modulating AD pathogenesis. One of the defining features of AD is the accumulation of amyloid-beta (Aβ) in the brain, which has a key role in the neurodegenerative cascade. Both testosterone and LH have been shown to modulate CNS Aβ accumulation in animal studies, and associations with cerebral amyloid load in human studies have supported this. The underlying mechanisms by which these hormones modulate Aβ accumulation and contribute to neurodegeneration are not completely understood, however they have been shown to regulate Aβ metabolism, enhance its clearance and alter the processing of its parent molecule, the amyloid precursor protein. This review will discuss underlying mechanisms ...
Testosterone replacement therapy (TRT) has been investigated in older men as a preventative treat... more Testosterone replacement therapy (TRT) has been investigated in older men as a preventative treatment against Alzheimer's disease and dementia. However, previous studies have been contradictory. We assessed TRT physiological effects in 44 older men (aged 61 ± 7.7 years) with subjective memory complaints using a double blind, randomized, crossover, placebo-controlled study. Participants were randomized into 2 groups, one group received transdermal testosterone (50 mg) daily for 24 weeks, followed by a 4 week wash-out period, then 24 weeks of placebo; the other group received the reverse treatment. Blood evaluation revealed significant increases in total testosterone, free (calculated) testosterone, dihydrotestosterone, and a decrease in luteinizing hormone levels (p<0.001) following TRT. Although there were significant increases in red blood cell counts, hemoglobin and prostate specific antigen levels following TRT, they remained within normal ranges. No significant differences in plasma amyloid beta, estradiol, sex hormone binding globulin, insulin levels, body fat percentage, or body mass index were detected. This is the first carefully controlled study that has investigated the influence of TRT in Indonesian men on blood biomarkers linked to dementia risk. Our study suggests TRT is safe and well-tolerated in this Indonesian cohort, yet longitudinal studies with larger cohorts are needed to assess TRT further, and to establish whether TRT reduces dementia risk.
The effect of testosterone on the levels of the Alzheimer's disease amyloid-beta peptide (Abe... more The effect of testosterone on the levels of the Alzheimer's disease amyloid-beta peptide (Abeta) was investigated in guinea pigs. Castrated guinea pigs (GPX) were administered testosterone at two different dosages, following which plasma and cerebrospinal fluid (CSF) Abeta_{40} levels were measured. Plasma Abeta_{40} levels were reduced in GPX in the early stages of low-dose testosterone treatment, whereas CSF Abeta_{40} levels were only reduced by the time circulating testosterone had returned to untreated GPX levels. The supraphysiological testosterone dose did not reduce CSF Abeta_{40} levels significantly until circulating testosterone was back to uncastrated levels, whereas plasma Abeta_{40} levels significantly increased over time in these animals. These results indicate that the extent of testosterone-induced changes to Abeta_{40} levels and their response rates depend on both the tissue examined and testosterone dosage.
Luteinizing hormone (LH) has been shown to alter the metabolism of beta amyloid (Aβ), a key prote... more Luteinizing hormone (LH) has been shown to alter the metabolism of beta amyloid (Aβ), a key protein in Alzheimer's disease (AD) pathogenesis. While LH and components required for LH receptor signalling are present in the brain, their role in the CNS remains unclear. In vitro, LH has been shown to facilitate neurosteroid production and alter Aβ metabolism. However, whether LH can directly modulate cerebral Aβ levels in vivo has not previously been studied. In this study, we investigated the effect of chronic administration of LH to the guinea pig CNS on cerebral Aβ levels. Gonadectomised male animals were administered, via cortical placement, either placebo or LH slow-release pellets. At 14 and 28 days after treatment, animals were sacrificed. Brain, plasma and CSF were collected and Aβ levels measured via ELISA. Levels of the Aβ precursor protein (APP) and the neurosteroidogenic enzyme cytochrome P450 side-chain cleavage enzyme (P450scc) were also assayed. An increase in CSF Aβ40 levels was observed 28 days following treatment. These CSF data also reflected changes in Aβ40 levels observed in brain homogenates. No change was observed in plasma Aβ40 levels but APP and its C-terminal fragments (APP-CTF) were significantly increased in response to LH exposure. Protein expression of P450scc was increased after 28 days of LH exposure, suggesting activation of the LH receptor. These data indicate that direct exposure of guinea pig CNS to LH results in altered brain Aβ levels, perhaps due to altered APP expression/metabolism.
The association between low testosterone levels and Alzheimer's d... more The association between low testosterone levels and Alzheimer's disease (AD) amyloid beta-peptide (Abeta) metabolism was investigated in brain and kidney of guinea pigs. The expression of Abeta peptide in the brain and kidney was assessed by using the immunohistochemistry method. No expression of Abeta was seen in both groups of animals. This negative staining was found until the fourth week following castration. The formation of Abeta in guinea pigs is perhaps not a short duration process and may undergo different metabolic pathway compare to humans. castration was not associated with the formation of Abeta in the brain and kidneys during a 1-month period and might require a longer period of time.
The association between low testosterone levels and Alzheimer's disease (AD) amyloid beta-pep... more The association between low testosterone levels and Alzheimer's disease (AD) amyloid beta-peptide (Abeta) metabolism was investigated in brain and kidney of guinea pigs. The expression of Abeta peptide in the brain and kidney was assessed by using the immunohistochemistry method. No expression of Abeta was seen in both groups of animals. This negative staining was found until the fourth week following castration. The formation of Abeta in guinea pigs is perhaps not a short duration process and may undergo different metabolic pathway compare to humans. castration was not associated with the formation of Abeta in the brain and kidneys during a 1-month period and might require a longer period of time.
CNS & neurological disorders drug targets, Jan 10, 2015
Reduction in testosterone levels in men during aging is associated with cognitive decline and ris... more Reduction in testosterone levels in men during aging is associated with cognitive decline and risk of dementia. Animal studies have shown benefits for testosterone supplementation in improving cognition and reducing Alzheimer's disease pathology. In a randomized, placebo-controlled, crossover study of men with subjective memory complaint and low testosterone levels, we investigated whether testosterone treatment significantly improved performance on various measures of cognitive functioning. Forty-four men were administered a battery of neuropsychological tests to establish the baseline prior to being randomly divided into two groups. The first group (Group A) received 24 weeks of testosterone treatment (T treatment) followed by 4 weeks washout, and then 24 weeks of placebo (P); the second group (Group B) received the same treatments, in reverse order (Placebo, washout, and then T treatment). In group A (TP), compared to baseline, there was a modest (1 point) but significant im...
Hormonal changes associated with ageing have been implicated in the pathogenesis of Alzheimer'... more Hormonal changes associated with ageing have been implicated in the pathogenesis of Alzheimer's disease (AD), the most common form of dementia. Reductions in serum testosterone and increases in luteinizing hormone (LH) are established AD risk factors for dementia in men and have important roles in modulating AD pathogenesis. One of the defining features of AD is the accumulation of amyloid-beta (Aβ) in the brain, which has a key role in the neurodegenerative cascade. Both testosterone and LH have been shown to modulate CNS Aβ accumulation in animal studies, and associations with cerebral amyloid load in human studies have supported this. The underlying mechanisms by which these hormones modulate Aβ accumulation and contribute to neurodegeneration are not completely understood, however they have been shown to regulate Aβ metabolism, enhance its clearance and alter the processing of its parent molecule, the amyloid precursor protein. This review will discuss underlying mechanisms ...
Testosterone replacement therapy (TRT) has been investigated in older men as a preventative treat... more Testosterone replacement therapy (TRT) has been investigated in older men as a preventative treatment against Alzheimer's disease and dementia. However, previous studies have been contradictory. We assessed TRT physiological effects in 44 older men (aged 61 ± 7.7 years) with subjective memory complaints using a double blind, randomized, crossover, placebo-controlled study. Participants were randomized into 2 groups, one group received transdermal testosterone (50 mg) daily for 24 weeks, followed by a 4 week wash-out period, then 24 weeks of placebo; the other group received the reverse treatment. Blood evaluation revealed significant increases in total testosterone, free (calculated) testosterone, dihydrotestosterone, and a decrease in luteinizing hormone levels (p<0.001) following TRT. Although there were significant increases in red blood cell counts, hemoglobin and prostate specific antigen levels following TRT, they remained within normal ranges. No significant differences in plasma amyloid beta, estradiol, sex hormone binding globulin, insulin levels, body fat percentage, or body mass index were detected. This is the first carefully controlled study that has investigated the influence of TRT in Indonesian men on blood biomarkers linked to dementia risk. Our study suggests TRT is safe and well-tolerated in this Indonesian cohort, yet longitudinal studies with larger cohorts are needed to assess TRT further, and to establish whether TRT reduces dementia risk.
The effect of testosterone on the levels of the Alzheimer's disease amyloid-beta peptide (Abe... more The effect of testosterone on the levels of the Alzheimer's disease amyloid-beta peptide (Abeta) was investigated in guinea pigs. Castrated guinea pigs (GPX) were administered testosterone at two different dosages, following which plasma and cerebrospinal fluid (CSF) Abeta_{40} levels were measured. Plasma Abeta_{40} levels were reduced in GPX in the early stages of low-dose testosterone treatment, whereas CSF Abeta_{40} levels were only reduced by the time circulating testosterone had returned to untreated GPX levels. The supraphysiological testosterone dose did not reduce CSF Abeta_{40} levels significantly until circulating testosterone was back to uncastrated levels, whereas plasma Abeta_{40} levels significantly increased over time in these animals. These results indicate that the extent of testosterone-induced changes to Abeta_{40} levels and their response rates depend on both the tissue examined and testosterone dosage.
Luteinizing hormone (LH) has been shown to alter the metabolism of beta amyloid (Aβ), a key prote... more Luteinizing hormone (LH) has been shown to alter the metabolism of beta amyloid (Aβ), a key protein in Alzheimer's disease (AD) pathogenesis. While LH and components required for LH receptor signalling are present in the brain, their role in the CNS remains unclear. In vitro, LH has been shown to facilitate neurosteroid production and alter Aβ metabolism. However, whether LH can directly modulate cerebral Aβ levels in vivo has not previously been studied. In this study, we investigated the effect of chronic administration of LH to the guinea pig CNS on cerebral Aβ levels. Gonadectomised male animals were administered, via cortical placement, either placebo or LH slow-release pellets. At 14 and 28 days after treatment, animals were sacrificed. Brain, plasma and CSF were collected and Aβ levels measured via ELISA. Levels of the Aβ precursor protein (APP) and the neurosteroidogenic enzyme cytochrome P450 side-chain cleavage enzyme (P450scc) were also assayed. An increase in CSF Aβ40 levels was observed 28 days following treatment. These CSF data also reflected changes in Aβ40 levels observed in brain homogenates. No change was observed in plasma Aβ40 levels but APP and its C-terminal fragments (APP-CTF) were significantly increased in response to LH exposure. Protein expression of P450scc was increased after 28 days of LH exposure, suggesting activation of the LH receptor. These data indicate that direct exposure of guinea pig CNS to LH results in altered brain Aβ levels, perhaps due to altered APP expression/metabolism.
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