The heat shock-induced hyperphosphorylation of τ is estrogen-independent and prevented by androgens: Implications for Alzheimer disease

Abstract

We have shown that heat shock induces rapid dephosphorylation of in both female and male rats followed by hyperphosphorylation only in female rats. To investigate the role of gonadal hormones, rats were ovariectomized (OVX), orchiectomized (ORX), or sham-gonadectomized and received replacement therapy with estradiol benzoate (EB), testosterone propionate (TP), or sesame oil (SO) vehicle for 2-3 weeks, respectively. At 0, 3, 6, and 12 hr after heat shock, immunoblot analysis of SDS cerebral extracts was performed using phosphate-dependent and -independent anti-antibodies. Seven groups of rats were analyzed: (i) sham-OVX ؉ SO; (ii) OVX ؉ SO; (iii) OVX ؉ EB; (iv) sham-ORX ؉ SO; (v) ORX ؉ SO; (vi) ORX ؉ TP; and (vii) ORX. In all seven groups, there was dephosphorylation of at 0 hr after heat shock. In all three groups of female rats, there was hyperphosphorylation of at 3 hr after heat shock, and its degree and temporal pattern were identical between the OVX ؉ SO and OVX ؉ EB groups. In male rats, there was hyperphosphorylation of at 3 hr after heat shock in both ORX ؉ SO and ORX groups, and its degree was reduced in the ORX ؉ TP group. Thus, dephosphorylation of is gonadal hormoneindependent, but while its hyperphosphorylation is estrogenindependent it is prevented by androgens. Because is abnormally hyperphosphorylated in Alzheimer disease, which is more frequent in women than men, these findings suggest that androgens may exert a neuroprotective effect.The prevalence of Alzheimer disease (AD) after age 65 is roughly two to three times higher in women than men (1). Because estrogens prevent neuronal atrophy (2), exert a neuroprotective effect against various toxic insults (3), and may synergize with neurotrophic factors (4-6), a deficiency of estrogens has been suggested to play a role in the pathogenesis of AD. However, estrogen neurotoxicity also has been postulated to be involved in brain aging and degeneration (7). So far, in many studies of postmenopausal women, demonstration of a beneficial effect of estrogen replacement therapy in reducing the risk or delaying the onset of AD has been controversial (8, 9). On the other hand, a possible advantageous role of androgens in reducing AD occurrence or severity has not been investigated yet. This is in spite of the century-old suggestion that androgens may rejuvenate aged men (10), the demonstration that androgens inhibit the stress response (11-13), and the increasing evidence that stressful stimuli play a role in the etiopathogenesis of AD (14-16).One histologic hallmark of AD is the neurofibrillary tangle. Neurofibrillary tangles are perikaryal aggregates of abnormal filaments, the so-called paired helical filaments, which consist mostly of abnormally hyperphosphorylated (17,18), and appear to be conjugated with the stress-inducible protein ubiquitin (16).is a group of Ϸ50-66-kDa phosphopolypeptides, but although many protein kinases and phosphatases have been described, the lack of appropriate animal models hindered so far the elucidation of the cascade...

Testosterone ameliorates streptozotocin-induced memory impairment in male rats

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“…Alzheimer's disease is also characterized by hyperphosphorylation of the intraneural tau protein, which causes the development of neural tangles. Testosterone is capable of preventing the hyperphosphorylation of tau protein [10,11] . A study on age-matched controls and patients with Alzheimer's disease demonstrated that the reduction in neurosteroids in most areas of the body, especially in cerebral neurons, was the cause of the disease [12] .…”

Androgens Regulate the Development of Neuropathology in a Triple Transgenic Mouse Model of Alzheimer's Disease

“…Androgens exert several actions in brain potentially associated with protection against AD, including neuroprotection (Pike, 2001) and attenuation of tau hyperphosphorylation (Papasozomenos, 1997). In addition, recent experimental findings indicate that androgens may reduce levels of soluble ␤-amyloid (A␤) (Goodenough et al, 2000;Gouras et al, 2000;Ramsden et al, 2003), the protein widely implicated in the initiation of AD pathogenesis (Hardy and Selkoe, 2002).…”

Alzheimer?s disease: the impact of age-related changes in reproductive hormones

“…AD is also characterized by neurofibrillary tangles composed of abnormally hyperphosphorylated bundles of tau protein inside neuronal cells. Testosterone is able to prevent the heat-shock hyperphosphorylation of tau protein [90]. The heat-shock effect on tau hyperphosphorlyation is mediated in part by glycogen synthase kinase-3 beta (GSK-3 beta), the activity of which is mediated by testosterone [91].…”