At the interface of sensory and motor dysfunctions and Alzheimer's disease.

Recent evidence indicates that sensory and motor changes may precede the cognitive symptoms of Alzheimer's disease (AD) by several years and may signify increased risk of developing AD. Traditionally, sensory and motor dysfunctions in aging and AD have been studied separately. To ascertain the evidence supporting the relationship between age-related changes in sensory and motor systems and the development of AD and to facilitate communication between several disciplines, the National Institute on Aging held an exploratory workshop titled "Sensory and Motor Dysfunctions in Aging and AD." The scientific sessions of the workshop focused on age-related and neuropathologic changes in the olfactory, visual, auditory, and motor systems, followed by extensive discussion and hypothesis generation related to the possible links among sensory, cognitive, and motor domains in aging and AD. Based on the data presented and discussed at this workshop, it is clear that sensory and motor regions of the central nervous system are affected by AD pathology and that interventions targeting amelioration of sensory-motor deficits in AD may enhance patient function as AD progresses.

γ-secretase binding sites in aged and Alzheimer's disease human cerebrum: the choroid plexus as a putative origin of CSF Aß.

Deposition of ß -amyloid (Aß) peptides, cleavage products of ß-amyloid precursor protein (APP) by ß-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer's disease (AD). γ-Secretase inhibition is a therapeutical anti-Aß approach, although changes in the enzyme's activity in AD brain are unclear. Cerebrospinal fluid (CSF) Aß peptides are thought to derive from brain parenchyma and thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aß efficacy. The present study compared active γ-secretase binding sites with Aß deposition in aged and AD human cerebrum, and explored the possibility of Aß production and secretion by the choroid plexus (CP). The specific binding density of [(3) H]-L-685,458, a radiolabeled high-affinity γ-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with similar ages and post-mortem delays. The CP in post-mortem samples exhibited exceptionally high [(3) H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and ß-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins and released Aß40 and Aß42 into the medium. Overall, our results suggest that γ-secretase activity appears unaltered in the cerebrum in AD and is not correlated with regional amyloid plaque pathology. The CP appears to be a previously unrecognised non-neuronal contributor to CSF Aß, probably at reduced levels in AD.

ß-Secretase-1 elevation in aged monkey and Alzheimer's disease human cerebral cortex occurs around the vasculature in partnership with multisystem axon terminal pathogenesis and ß-amyloid accumulation.

Alzheimer's disease (AD) is the most common dementia-causing disorder in the elderly; it may be related to multiple risk factors, and is characterized pathologically by cerebral hypometabolism, paravascular ß-amyloid peptide (Aß) plaques, neuritic dystrophy, and intra-neuronal aggregation of phosphorylated tau. To explore potential pathogenic links among some of these lesions, we examined ß-secretase-1 (BACE1) alterations relative to Aß deposition, neuritic pathology and vascular organization in aged monkey and AD human cerebral cortex. Western blot analyses detected increased levels of BACE1 protein and ß-site-cleavage amyloid precursor protein C-terminal fragments in plaque-bearing human and monkey cortex relative to controls. In immunohistochemistry, locally elevated BACE1 immunoreactivity (IR) occurred in AD but not in control human cortex, with a trend for increased overall density among cases with greater plaque pathology. In double-labeling preparations, BACE1 IR colocalized with immunolabeling for Aß but not for phosphorylated tau. In perfusion-fixed monkey cortex, locally increased BACE1 IR co-existed with intra-axonal and extracellular Aß IR among virtually all neuritic plaques, ranging from primitive to typical cored forms. This BACE1 labeling localized to swollen/sprouting axon terminals that might co-express one or another neuronal phenotype markers (GABAergic, glutamatergic, cholinergic, or catecholaminergic). Importantly, these BACE1-labeled dystrophic axons resided near to or in direct contact with blood vessels. These findings suggest that plaque formation in AD or normal aged primates relates to a multisystem axonal pathogenesis that occurs in partnership with a potential vascular or metabolic deficit. The data provide a mechanistic explanation for why senile plaques are present preferentially near the cerebral vasculature.

Functional deprivation promotes amyloid plaque pathogenesis in Tg2576 mouse olfactory bulb and piriform cortex.

Cerebral hypometabolism and amyloid accumulation are principal neuropathological manifestations of Alzheimer's disease (AD). Whether and how brain/neuronal activity might modulate certain pathological processes of AD are interesting topics of recent clinical and basic research in the field, and may be of potential medical relevance in regard to both the disease etiology and intervention. Using the Tg2576 transgenic mouse model of AD, this study characterized a promotive effect of neuronal hypoactivity associated with functional deprivation on amyloid plaque pathogenesis in the olfactory pathway. Unilateral naris-occlusion caused beta-secretase-1 (BACE1) elevation in neuronal terminals in the deprived relative to the non-deprived bulb and piriform cortex in young adult mice. In parallel with the overall age-related plaque development in the forebrain, locally increased BACE1 immunoreactivity co-occurred with amyloid deposition first in the piriform cortex then within the bulb, more prominent on the deprived relative to the non-deprived side. Biochemical analyses confirmed elevated BACE1 protein levels, enzymatic activity and products in the deprived relative to non-deprived bulbs. Plaque-associated BACE1 immunoreactivity in the bulb and piriform cortex was localized preferentially to swollen/sprouting glutamatergic axonal terminals, with Abeta immunoreactivity occurring inside as well as around these terminals. Together, these findings suggest that functional deprivation or neuronal hypoactivity facilitates amyloid plaque formation in the forebrain in a transgenic model of AD, which operates synergistically with age effect. The data also implicate an intrinsic association of amyloid accumulation and plaque formation with progressive axonal pathology.

Beta-secretase-1 elevation in transgenic mouse models of Alzheimer's disease is associated with synaptic/axonal pathology and amyloidogenesis: implications for neuritic plaque development.

The presence of neuritic plaques is a pathological hallmark of Alzheimer's disease (AD). However, the origin of extracellular beta-amyloid peptide (Abeta) deposits and the process of plaque development remain poorly understood. The present study attempted to explore plaque pathogenesis by localizing beta-secretase-1 (BACE1) elevation relative to Abeta accumulation and synaptic/neuritic alterations in the forebrain, using transgenic mice harboring familial AD (FAD) mutations (5XFAD and 2XFAD) as models. In animals with fully developed plaque pathology, locally elevated BACE1 immunoreactivity (IR) coexisted with compact-like Abeta deposition, with BACE1 IR occurring selectively in dystrophic axons of various neuronal phenotypes or origins (GABAergic, glutamatergic, cholinergic or catecholaminergic). Prior to plaque onset, localized BACE1/Abeta IR occurred at swollen presynaptic terminals and fine axonal processes. These BACE1/Abeta-containing axonal elements appeared to undergo a continuing process of sprouting/swelling and dystrophy, during which extracellular Abeta IR emerged and accumulated in surrounding extracellular space. These data suggest that BACE1 elevation and associated Abeta overproduction inside the sprouting/dystrophic axonal terminals coincide with the onset and accumulation of extracellular amyloid deposition during the development of neuritic plaques in transgenic models of AD. Our findings appear to be in harmony with an early hypothesis that axonal pathogenesis plays a key or leading role in plaque formation.

Apolipoprotein E may be a critical factor in hormone therapy neuroprotection.

In this review we examine the evidence for ovarian hormone neuroprotection in chronic neurological diseases, including stroke. We propose that neuroprotection may involve the ability of estrogens to modulate apolipoprotein E (apoE) and its receptor, the low density lipoprotein receptor related protein (LRP). Results from numerous studies have demonstrated that (1) nerve regeneration is severely delayed in apoE-gene knockout (KO) mice as compared to wild-type (WT) littermates; (2) 17beta estradiol replacement in ovariectomized mice resulted in a significant increase in levels of apoE and LRP, in the olfactory bulb (OB) and other brain areas; (3) estradiol treatment increased both apoE and neurite outgrowth in cortical and olfactory neuronal cultures; and (4) estradiol treatment had no effect on neurite outgrowth in cultures deprived of apoE or in the presence of apoE4. In essence these studies suggest that apoE is a critical intermediary for the beneficial effects of 17beta estradiol on nerve repair, which can lead to functional reorganization (plasticity). Future studies of HT should evaluate the effects of apoE genotype and production estradiol on neuroprotection.

Impact of apoE deficiency during synaptic remodeling in the mouse olfactory bulb.

In this study we examined the role of apoE on the rate of synaptic recovery in the olfactory bulb (OB) following olfactory epithelium (OE) lesioning in mice. We used both immunoblotting and immunohistochemical techniques to compare the density of OB synaptophysin (Syn, a synaptic marker) in apoE-gene deficient/knockout (KO) mice and wild-type (WT) mice following OE lesion. We found that the whole bulb concentrations of Syn, measured by immunoblotting, declined sharply following injury in both WT and KO mice during the degenerative phase (3-7 days). After this initial decline, the Syn concentration gradually increased to normal levels by 56 days in WT mice. In contrast, Syn concentration in KO mice did not recover by day 56 when Syn density in WT was essentially normal. Glomerular Syn density, measured by immunohistochemistry, found a lower density in KO mice at all time points post-lesion. This lower concentration of whole bulb Syn parallels the slower recovery of glomerular area in KO mice. The data indicate that apoE deficiency in KO mice is associated with a delayed recovery of the glomerular area and a slower recovery in Syn concentration in the OB.

beta-Secretase expression in normal and functionally deprived rat olfactory bulbs: inverse correlation with oxidative metabolic activity.

Cerebral hypometabolism, mitochondrial dysfunction, and beta-amyloid peptide (Abeta) accumulation are well-characterized manifestations of Alzheimer's disease (AD). beta-Secretase (BACE) is a prerequisite for amyloidogenesis, and it is up-regulated in sporadic AD. To explore a potential in vivo mechanism by which Abeta production is modulated by neuronal activity and/or oxidative metabolism, we compared BACE expression with cytochrome c oxidase (CO) or succinic dehydrogenase (SDH) activity in normal and functionally deprived adult rat olfactory bulb. In normal bulb, BACE was expressed predominantly in the glomerular layer, but labeling intensity within individual glomeruli varied substantially. A strong negative correlation existed between BACE labeling intensity and CO or SDH activity among individual glomeruli. Unilateral naris occlusion resulted in elevated glomerular BACE labeling in the deprived bulbs relative to the nondeprived counterparts, which was correlated with decreased CO activity in the same anatomic location. Enhanced BACE labeling was confirmed by measurements of elevated protein levels, enzymatic activity, and beta-site cleavage products of amyloid precursor protein in bulb extracts. Our findings reveal a negative regulation of BACE expression by physiological neuronal activity and an intrinsic inverse correlation between BACE expression and oxidative metabolism at the first synapse on the olfactory pathway. The results point to a biological role of BACE in synapse function and plasticity as well as a potential mechanism whereby reduced neuronal activity or metabolism could lead to amyloid overproduction in synaptic terminals.

Estradiol regulation of astroglia and apolipoprotein E: an important role in neuronal regeneration.

The effects of ovarian hormone on neuronal growth and function are well known. However, equally important, but often neglected, are ovarian hormone effects on glia. Our in vivo and in vitro studies show that estradiol modifies both neuronal growth and glial activity and these effects are tightly linked. Estradiol stimulates neurite growth and the release of the glial apolipoprotein E (apoE) in culture studies. Estradiol-stimulated neurite growth in these cultures requires apoE. Estradiol replacement in ovariectomized mice transiently increases the expression of apoE, the low density lipoprotein receptor related protein (LRP) and synaptophysin throughout the brain. Continuous estradiol replacement over two months loses effect on apoE, LRP, and synaptophysin and suppresses reactive gliosis. Estrous cycle variation of glial activation (GFAP) and apoE are not identical. We propose that estradiol (and other ovarian hormones) functions as a zeitgeber to co-ordinate neuronal-glial interactions. Co-ordination assures temporally appropriate excitatory and inhibitory interactions between glia and neurons. With aging and the loss of ovarian cyclicity, some of this co-ordination must be diminished. These observations present significant clinical implications. Approaches to hormone therapy (HT), for diminishing the risk of chronic neurological diseases, need to consider the temporal nature of ovarian hormones in brain repair and plasticity. Moreover, approaches must consider apoE genotype. The neuroprotective effects of HT in numerous chronic age-related diseases may represent effective co-ordination of repair processes rather than direct disease-specific actions. Moreover, the role of glial-derived proteins in neuroprotection should not be ignored.

The distribution of apolipoprotein E in mouse olfactory epithelium.

Previous studies from our laboratory suggest that apolipoprotein (apoE), a lipid transporting protein, facilitates olfactory nerve regeneration. We have shown that apoE is enriched in the olfactory nerve and around the glomeruli of the olfactory bulb (OB). The studies reported herein were undertaken to identify possible sources of apoE in the olfactory epithelium (OE). Immunoblotting results revealed apoE expression in the OE of wild-type (WT) mice, but not in apoE deficient/knockout (KO) mice. Immunohistochemical studies revealed that the perikarya and processes of sustentacular (Sus) cells expressed apoE-like immunoreactivity. Minimal neuronal apoE immunostaining was seen, although apoE was observed in the interstial spaces between olfactory receptor neurons (ORN). Substantial apoE-like immunoreactivity was localized to the endfeet and terminal process of Sus cells surrounding the basal cells. Double labeling immunocytochemical studies confirmed that the cell bodies and endfeet of Sus cells expressed high levels of apoE. The endothelial cells of blood vessels were intensely stained for apoE in the lamina propria. Cells forming Bowman's gland also immunostained for apoE. The apoE staining in the nerve fascicles was less intense, but was uniformly distributed throughout the core of the nerve bundles. Heavily stained cells, probably ensheathing glia, surrounded the nerve fascicles. These results revealed that apoE is expressed in the adult OE and lamina propria at strategic locations where it could facilitate the differentiation, maturation and axonal growth of the ORN, perhaps by recycling lipids from degenerating ORN for use by growing axons.

[3H]-L-685,458 as a radiotracer that maps gamma-secretase complex in the rat brain: relevance to Abeta genesis and presence of active presenilin-1 components.

Gamma-secretase is a multimeric enzyme important for normal cell/neuronal proliferation, differentiation and plasticity. Determining in vivo gamma-secretase expression and activity remains a challenge because its subunit proteins can exist in immature and preassembled forms, but may execute cellular roles irrelevant to gamma-site cleavage. In this study, we characterized [3H]-L-685,458 as a radiotracer for the detection of active gamma-secretase in adult rat brain. In vitro autoradiography indicated that [3H]-L-685,458 binding was saturatable, displaceable by peptidomimetic and small molecule gamma-secretase inhibitors, and exhibited rapid association and dissociation kinetics. In cultured hippocampal slices, [3H]-L-685,458 binding density correlated with Abeta reduction following in-dish dosing of this radioligand or a non-radioactive gamma-secretase inhibitor. [3H]-L-685,458 binding sites in the adult brain were differentially distributed across regions and laminas, with heavy binding localized to the olfactory glomeruli, hippocampal CA3 and cerebellar molecular layer, and moderate binding in the cerebral cortex, amygdala and selected subcortical regions. All of these regions showed labeling for presenilin-1 N-terminal fragments (PS1-NTFs). A distinct correlation of dense binding sites with abundant presence of PS1-NTFs was verified in hippocampal mossy fiber terminals and olfactory bulb glomeruli, suggestive of a rich expression of gamma-secretase in the synapses at these locations that are characteristic of dynamic plasticity. Together, [3H]-L-685,458 is an excellent radiotracer for mapping active gamma-secretase complex, and may serve as a useful tool for studying the enzyme in vivo and in vitro.

Estradiol replacement increases the low-density lipoprotein receptor related protein (LRP) in the mouse brain.

Numerous epidemiology studies have shown protective effects of hormone therapy (HT) on chronic neurological diseases. We have proposed that some of the neuroprotective effects of estrogen are mediated by apolipoprotein E (apoE). Polymorphisms of receptors for apoE modify the risk for dementia. To our knowledge, no reports exist showing CNS effects of estrogen replacement on members of the low-density lipoprotein receptor family. The current study focused on the effect of estradiol-17beta (E2) replacement on protein expression of two members of the receptor family, the low-density lipoprotein receptor (LDL-r) and low-density lipoprotein receptor related protein (LRP) in ovariectomized mice. Five days of E2 replacement significantly increased LRP expression in the hippocampus, olfactory bulb and neocortex but not in cerebellum. In contrast, E2 treatment decreased LDL-r protein expression in olfactory bulb. HT modification of both apoE and LRP could have wide-spread effects on cellular function given LRP's manifold signaling functions.

Delayed olfactory nerve regeneration in ApoE-deficient mice.

Apolipoprotein E (apoE), a lipid transporting protein, is extensively expressed in the primary olfactory pathway, but its function is unknown. We previously reported increased apoE levels in the olfactory bulb (OB) following olfactory epithelium (OE) lesion in mice, and hypothesized that apoE may play a vital role in olfactory nerve (ON) regeneration. To directly test this hypothesis, we examined the rate of ON regeneration following OE lesion in apoE deficient/knockout (KO) and wild-type (WT) mice. OE was lesioned in 2- to 3-month-old mice by intranasal irrigation with Triton X-100 (TX). OB were collected at 0, 3, 7, 21, 42, and 56 days post-lesion. OB recovery was measured by both immunoblotting and immunohistochemical analysis of growth cone associated protein (GAP) 43 and olfactory marker protein (OMP). The results revealed that (1) OMP recovery in the OB was significantly slower in apoE KO compared to WT mice; (2) recovery of glomerular area was similarly slower; and (3) GAP43 increases and return to prelesion levels in the OB were slower in KO mice. Together, these results show that olfactory nerve regeneration is significantly slower in KO mice as compared to WT mice, suggesting apoE facilitates olfactory nerve regeneration.

Estrogen facilitates neurite extension via apolipoprotein E in cultured adult mouse cortical neurons.

Literature review suggests a close relationship between estrogen and apolipoprotein E (ApoE) in the central nervous system. Epidemiology studies show that estrogen replacement therapy (ERT) decreases the morbidity from several chronic neurological diseases. Alleles of ApoE modify the risk for and progression of the same diseases. ApoE levels in the rodent brain vary during the estrous cycle and increase after 17beta-estradiol administration. Both estradiol and ApoE3, the most common isoform of human ApoE, increase the extent of neurite outgrowth in culture. Combined, these observations suggest a common mechanism whereby estrogen may increase ApoE levels to facilitate neurite growth. We tested this hypothesis by characterizing the effects of estradiol and ApoE isoforms on neurite outgrowth in cultured adult mouse cortical neurons. Estradiol increased ApoE levels and neurite outgrowth. ApoE2 increased neurite length more so than ApoE3 in the presence of estradiol. Estradiol had no effect on neurite outgrowth from mice lacking the ApoE gene or when only ApoE4, the isoform of ApoE that is associated with increased risk of neurological disease, was exogenously supplied. Cultures from mice transgenic for human ApoE3 or ApoE4 showed the same isoform-specific effect. Neuronal internalization of recombinant human ApoE3 was greater than ApoE4, and ApoE3 was more effective than ApoE4 in facilitating neuronal uptake of a fatty acid. We conclude that estradiol facilitates neurite growth through an ApoE-dependent mechanism. The effects of ERT on chronic neurological diseases may vary with ApoE genotype. The clinical use of ERT may require ApoE genotyping for optimal efficacy.

Olfactory function in apoE knockout mice.

Apolipoprotein E (apoE), a lipid transporting protein, has been shown to play a vital role in nerve repair and remodeling. Since the olfactory system is in a continuous state of remodeling, the present study tested the hypothesis that apoE is required for normal functioning of the olfactory system. Olfactory behavior of wild-type (WT) and apoE-deficient (apoE KO) mice was assessed by using three standard olfactory tests: (1) the buried food pellet (BFP) test; (2) the odor choice (OC) test; and (3) the odor cued taste avoidance (OCTA) test. ApoE KO mice performed poorly in all the three tests as compared to WT mice, although they learned the tasks at a rate comparable to WT mice. ApoE KO mice had a significantly longer latency to find the buried pellet than WT mice. In the OC experiment, apoE KO mice did not differentiate water from an odorant solution. Furthermore, in the OCTA test the apoE KO mice were significantly less successful than WT mice at avoiding water containing an odorant and a bad tastant. These data demonstrate that apoE deficiency in apoE KO mice leads to a deficit in olfactory function, suggesting an important role for apoE in the olfactory system.

Apolipoprotein E4 inhibits, and apolipoprotein E3 promotes neurite outgrowth in cultured adult mouse cortical neurons through the low-density lipoprotein receptor-related protein.

The apolipoprotein E4 (apoE4) genotype is a major risk factor for Alzheimer's disease (AD); however, the mechanism is unknown. We previously demonstrated that apoE isoforms differentially modulated neurite outgrowth in embryonic neurons and in neuronal cell lines. ApoE3 increased neurite outgrowth whereas apoE4 decreased outgrowth, suggesting that apoE4 may directly affect neurons in the brain. In the present study we examined the effects of apoE on neurite outgrowth from cultured adult mouse cortical neurons to examine if adult neurons respond the same way that embryonic cells do. The results from this study demonstrated that (1) cortical neurons derived from adult apoE-gene knockout (apoE KO) mice have significantly shorter neurites than neurons from adult wild-type (WT) mice; (2) incubation of cortical neurons from adult apoE KO mice with human apoE3 increased neurite outgrowth, whereas human apoE4 decreased outgrowth in a dose-dependent fashion; (3) the isoform specific effects were abolished by incubation of the neurons with either receptor associated protein (RAP) or lactoferrin, both of which block the interaction of apoE-containing lipoproteins with the low-density lipoprotein receptor-related protein (LRP). These data suggest a potential mechanism whereby apoE4 may play a role in regenerative failure and accelerate the development of AD.

Effect of Neuregen nutrient medium on survival of cortical neurons after aspiration lesion in rats.

OBJECT: During brain surgery, it would be beneficial to irrigate the surgical cavity with a solution that promotes neuronal growth and survival. The authors find that incubation of cultured neurons with normal saline, also known as buffered salts, which are often used in brain surgery in humans, does not support neuron survival. Neuregen is an optimized serum-free culture medium that promotes regeneration of adult rat and human central nervous system neurons in vitro. It includes balanced salts, glucose, amino acids, vitamins, essential fatty acids, hormones, antioxidants, and other ingredients. The authors hypothesize that brain lesions irrigated and soaked in Neuregen nutrients will have better neuron survival rates in deafferented regions than lesions irrigated with saline. METHODS: Lesioning of the rat fimbria-fornix area was achieved by aspiration through the cortex; animals were killed 4 weeks later. Brain sections were stained with cresyl violet for neuron counts in the medial septum and cortex. Treatment of the lesion cavity with Neuregen resulted in a 55% increase in neuron density in the septum compared with saline treatment (p = 0.02). Cortical lesions treated with Neuregen showed a 27% increase in neuron density compared with saline-treated lesions (p = 0.015); the neuron density in Neuregen-treated rat brains was equivalent to that seen with sham treatment. Efficacy of Neuregen with basic fibroblast growth factor (bFGF) was significantly better than with Dulbecco modified Eagle medium bFGF, but not better than Neuregen alone. Neuregen produced a coincidental fourfold reduction in glial fibrillary acidic protein immunoreactivity at 4 weeks compared with saline (p = 0.002), to levels equivalent to those found in sham lesions. CONCLUSIONS: These results indicate that a highly optimized nutrient medium promotes neuron survival after brain surgery.

Long-term effects of estradiol replacement in the olfactory system.

Olfactory dysfunction often precedes other clinical symptoms in chronic neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. Estrogen deficiency and apoE genotype are known risk factors in these diseases and these factors also affect olfaction. Therefore we examined the effects of estradiol replacement following ovariectomy on expression of apoE and markers of cell proliferation, neuronal maturation, synaptogenesis and reactive gliosis in the primary olfactory pathway of wild-type (WT) and apoE knockout (KO) mice. Estradiol replacement increased apoE staining in the olfactory nerve and glomerular layers. Estradiol increased astrocyte density and olfactory epithelium (OE) thickness regardless of the genotype. In addition estradiol treatment increased the number of mature neurons in the OE and glomerular synaptophysin in both genotypes, but the magnitude of increase was greater in the WT than in the KO mice. These data suggest that estrogen and apoE act synergistically to minimize the loss of mature sensory neurons and synapses following ovariectomy.

BACE1 elevation is involved in amyloid plaque development in the triple transgenic model of Alzheimer's disease: differential Aß antibody labeling of early-onset axon terminal pathology.

ß-amyloid precursor protein (APP) and presenilins mutations cause early-onset familial Alzheimer's disease (FAD). Some FAD-based mouse models produce amyloid plaques, others do not. ß-Amyloid (Aß) deposition can manifest as compact and diffuse plaques; it is unclear why the same Aß molecules aggregate in different patterns. Is there a basic cellular process governing Aß plaque pathogenesis? We showed in some FAD mouse models that compact plaque formation is associated with a progressive axonal pathology inherent with increased expression of ß-secretase (BACE1), the enzyme initiating the amyloidogenic processing of APP. A monoclonal Aß antibody, 3D6, visualized distinct axon terminal labeling before plaque onset. The present study was set to understand BACE1 and axonal changes relative to diffuse plaque development and to further characterize the novel axonal Aß antibody immunoreactivity (IR), using triple transgenic AD (3xTg-AD) mice as experimental model. Diffuse-like plaques existed in the forebrain in aged transgenics and were regionally associated with increased BACE1 labeled swollen/sprouting axon terminals. Increased BACE1/3D6 IR at axon terminals occurred in young animals before plaque onset. These axonal elements were also co-labeled by other antibodies targeting the N-terminal and mid-region of Aß domain and the C-terminal of APP, but not co-labeled by antibodies against the Aß C-terminal and APP N-terminal. The results suggest that amyloidogenic axonal pathology precedes diffuse plaque formation in the 3xTg-AD mice, and that the early-onset axonal Aß antibody IR in transgenic models of AD might relate to a cross-reactivity of putative APP ß-carboxyl terminal fragments.

Acute responses to estradiol replacement in the olfactory system of apoE-deficient and wild-type mice.

Epidemiological studies suggest that estrogen therapy protects against clinical expression of chronic neurological diseases. These beneficial effects of estrogen therapy are highly modified by apolipoprotein E (apoE) through an unknown mechanism. We examined the short-term effects of estradiol replacement in ovariectomized mice on apoE expression and markers for cell proliferation, reactive gliosis, neuronal maturation, and synaptogenesis in the primary olfactory pathway of wild-type (WT) and apoE knockout (KO) mice. Three days of estradiol replacement increased apoE expression in the olfactory nerve and in the glomerular layer. Estradiol treatment also increased cell proliferation, total cell numbers, number of mature neurons in the olfactory epithelium, and reactive astrocyte numbers in the olfactory bulb (OB) in both WT and KO mice. We also found that estradiol increased glomerular synaptophysin (Syn), but the magnitude of increase was potentiated by the presence of apoE. These data suggest that apoE may be necessary to elicit the complete effect of estradiol on Syn upregulation.