Female Sex and Alzheimer's Risk: The Menopause Connection.

Along with advanced age and apolipoprotein E (APOE)-4 genotype, female sex is a major risk factor for developing late-onset Alzheimer's disease (AD). Considering that AD pathology begins decades prior to clinical symptoms, the higher risk in women cannot simply be accounted for by their greater longevity as compared to men. Recent investigation into sex-specific pathophysiological mechanisms behind AD risk has implicated the menopause transition (MT), a midlife neuroendocrine transition state unique to females. Commonly characterized as ending in reproductive senescence, many symptoms of MT are neurological, including disruption of estrogen-regulated systems such as thermoregulation, sleep, and circadian rhythms, as well as depression and impairment in multiple cognitive domains. Preclinical studies have shown that, during MT, the estrogen network uncouples from the brain bioenergetic system. The resulting hypometabolic state could serve as the substrate for neurological dysfunction. Indeed, translational brain imaging studies demonstrate that 40-60 year-old perimenopausal and postmenopausal women exhibit an AD-endophenotype characterized by decreased metabolic activity and increased brain amyloid-beta deposition as compared to premenopausal women and to age-matched men. This review discusses the MT as a window of opportunity for therapeutic interventions to compensate for brain bioenergetic crisis and combat the subsequent increased risk for AD in women.

The women's health initiative estrogen replacement therapy is neurotrophic and neuroprotective.

The current study investigated the neurotrophic and neuroprotective action of the complex formulation of conjugated equine estrogens (CEEs), the most frequently prescribed estrogen replacement therapy in the United States and the estrogen replacement therapy of the Women's Health Initiative. Morphologic analyses demonstrated that CEEs significantly increased neuronal outgrowth in hippocampal, basal forebrain, occipital, parietal and frontal cortex neurons. Dose-response analyses indicated that the lowest effective concentration of CEEs exerted the maximal neurotrophic effect with greatest potency occurring in hippocampal and occipital cortex neurons. CEES induced highly significant neuroprotection against beta amyloid(25-35), hydrogen peroxide and glutamate-induced toxicity. Rank order of potency and magnitude of CEE-induced neuroprotection in the brain regions investigated was hippocampal neurons > basal forebrain neurons > cortical neurons. In hippocampal neurons pre-exposed to beta amyloid(25-35), CEEs halted Abeta(25-35)-induced cell death and protected surviving neurons from further cell death induced by Abeta(25-35). Because CEEs are the estrogen replacement therapy of the Women's Health Initiative, results of the current study could provide cellular mechanisms for understanding effects of CEEs on cognitive function and risk of Alzheimer's disease derived from this prospective clinical trial.

Advances and challenges in the prevention and treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia and accounts for one-half to three-fourths of all cases of dementia. In the United States, AD is the leading cause of a loss of independent living and subsequent institutionalization. Approximately 4 million Americans are currently diagnosed with Alzheimer's disease-which results in greater than $100 billion dollars in health care costs. This review provides a description of the cognitive and neuropathological features of AD and the challenge that aging populations around the globe pose to health care systems and to societies. A review of new and promising therapeutic strategies for the prevention of AD is discussed which includes estrogen replacement therapy and anti-inflammatory therapeutics. Pharmaceutical approaches that delay the progression of the disease, such as antioxidants, are discussed as well as therapeutic strategies for improvement of cognitive function in AD patients, including the new generation of compounds aimed at enhancing cholinergic function. This section is followed by a review of the current status on nerve growth factor trials. The final section addresses the issue of the genetic linkages of AD, the impact of transgenic and gene knockout mouse models of AD on research in the field and the potential use of gene therapy to treat AD.

Vasopressin in the mammalian brain: the neurobiology of a mnemonic peptide.

We have sought to understand the mechanisms by which VP can enhance memory function and in the process determine whether VP fulfills the requirements for neurotransmitter status. The latter goal of proving the neurotransmitter status of VP has been achieved through our findings and the results of many of the scientists contributing to this volume. With respect to elucidating the mechanisms by which VP can enhance memory function, results of our work have shown that VP and its receptors are present in brain regions known to be involved in memory function, that release of VP is inhibited by a factor that inhibits memory function, that VP can significantly enhance the morphological complexity and outgrowth of neurons involved in memory function, that second messenger systems held to be involved in learning and memory, cyclic AMP and calcium signaling pathways, are potentiated and activated by VP, that electrophysiological models of memory function are induced by VP, and that when animals remember a learned association VP content in brain increases over time during the active phase of remembering. Collectively, these studies have taught us a great deal about the sites and mechanisms of VP action and have led us to pursue avenues of investigation that we would not have imagined 15 years ago when we began this work. We stand on the threshold of a new era in our research as we begin our studies of the role VP and its receptors play in the cerebral cortex. Thus far, results of these studies are quite exciting and promise to yield fascinating insights into the complexities of VP action in the most highly developed region of the mammalian brain, the cerebral cortex, the site of abstract reasoning, judgment, complex analysis and the repository of those memories that last a life-time.

Vasopressin induction of long-lasting potentiation of synaptic transmission in the dentate gyrus.

Vasopressin receptors are present in both the developing and mature dentate gyrus of the rat brain and are of the V1 vasopressor type. Because vasopressin has been shown to influence memory function when injected into the dentate gyrus, the influence of this peptide on an electrophysiological model of learning and memory using the field excitatory postsynaptic potential (EPSP) of the dentate gyrus was investigated. Results of these studies showed that nanomolar concentrations of [Arg8]-vasopressin induced a prolonged increase in the amplitude and slope of the evoked population response in the presence of 1.5 mM calcium. Moreover, the expression of the vasopressin-induced potentiation of the EPSP persisted following removal of vasopressin from the perfusion medium. The vasopressin-induced sustained increase has been termed long-term vasopressin potentiation (LTVP). The closely related neuropeptide oxytocin had no effect upon the EPSP of the dentate gyrus. Preincubation of hippocampal slices in a selective V1 antagonist blocked the expression of LTVP. The ability of the V1 antagonist to block LTVP demonstrates that the potentiation induced by vasopressin is receptor-specific. In the presence of 2.5 mM calcium, the effect of vasopressin was opposite to that observed in 1.5 mM calcium. Under the conditions of 2.5 calcium, vasopressin induced a prolonged depression in the amplitude and slope of the EPSP. Expression of both potentiation and depression appeared within 5 minutes of application and persisted for the length of the observation, 60 minutes. These experiments demonstrate that vasopressin can induce long-lasting changes in the excitability of dentate gyrus neurons that are both calcium-dependent and receptor-specific.

Vasopressin-induction of cyclic AMP in cultured hippocampal neurons.

We investigated the influence of AVP on the induction of the second messenger cyclic AMP (cAMP) during early hippocampal neuron development using cultured hippocampal neurons. Results of those studies revealed that in cultured hippocampal neurons AVP-induces the formation of the second messenger cyclic AMP (cAMP). AVP-induction of cAMP is dose dependent and displays an inverted-U shaped function. Maximal AVP-induction of cAMP accumulation occurred following 15 min of exposure. Results of peptide specificity studies indicated that the vasopressin receptor expressed in cultured hippocampal neurons is pharmacologically promiscuous in that vasopressin metabolite peptides, oxytocin, a V2 receptor agonist and antagonist can all induce the formation of cAMP. In marked contrast, [Phe2,Ile3,Orn8]-vasopressin, a V1 receptor agonist, did not induce cAMP formation. The expression of the cAMP-linked AVP receptor is transient with maximal functional expression occurring between 3 and 4 days in culture which recedes by the fifth day in culture. Because the peptide specificity of the cAMP-linked neural AVP receptor is unique, relative to all other AVP receptors studied thus far, we suggest the term V2b receptor to indicate the distinction of a third (3) type of AVP receptor which is expressed during development (D) of hippocampal nerve cells.