The contribution of cerebral vascular semicarbazide-sensitive amine oxidase to cerebral amyloid angiopathy in Alzheimer's disease

Semicarbazide-sensitive amine oxidase (SSAO) catalyses the oxidative deamination of a variety of endogenous substrates, such as methylamine and aminoacetone, to produce highly reactive aldehydes, which are capable of inducing protein cross-linkage, beta amyloid (Aβ) aggregation and advanced glycation end-product formation. In the brain, SSAO is exclusively located on the blood vessels. Deposits of Aβ, the hallmark of Alzheimer's disease (AD), are closely associated with cerebral blood vessels, that is, cerebral amyloid angiopathy (CAA). In the present study, we examined whether SSAO-mediated deamination contributes to CAA in AD. We employed immunohistochemistry to examine the colocalization of SSAO and Aβ in post mortem brains of AD patients. To assess the role of SSAO-mediated deamination in the deposition of Aβ on blood vessel walls, we developed an in vitro blood vessel model using sections of human umbilical cord. We found a strong expression of SSAO colocalized with Aβ deposits on the blood vessels in AD brains. We also demonstrated that SSAO-mediated deamination increases the deposition of Aβ onto blood vessel walls. Our results support the hypothesis that cerebral vascular SSAO-catalysed deamination contributes to CAA in AD brains.     

Ubiquitin in cerebral amyloid angiopathy.

Immunohistological findings in cerebral blood vessels of 4 cases with cerebral amyloid angiopathy (CAA) were compared with those of 4 Alzheimer's (AD) cases. A panel of antibodies against 2 neurofilament subunits (BF10 and RT97), a microtubule-associated protein (TAU) and ubiquitin were used. CAA cases showed a strong immunoreactivity for ubiquitin in blood vessel wall. Senile plaques (SPs) in CAA cases showed strong ubiquitin positivity but the central amyloid core was negative. AD brains showed immunoreactivity with all antibodies in SPs and neurofibrillary tangles (NFTs); blood vessels were consistently negative for ubiquitin. Control brains showed few SPs and NFTs; these were positive for ubiquitin, but blood vessels were negative. These results indicate that vascular amyloid deposition in CAA and AD may have different pathophysiological mechanisms.     

High-affinity choline uptake carrier in Alzheimer''s disease: implications for the cholinergic hypothesis of dementia

We examined the density and the state of affinity of [3H]hemicholinium-3 ([3H]HC-3) binding sites, a marker of the presynaptic high-affinity choline uptake (HACU) carrier, in 4 representative regions of 13 postmortem Alzheimer's disease (AD) brains, as well as in 12 matched control brains. Significant reductions in the densities of [3H]HC-3 binding sites were found both in frontal cortex (-44.7%) and hippocampus (-36.5%) of AD brains in comparison to controls. On the other hand the densities of [3H]HC-3 binding sites in AD brains in caudate-putamen and cerebellar cortex showed no significant differences when compared to controls. No significant change in the state of affinity of these sites could be observed in the saturation assays carried out in hippocampus and frontal cortex. Our findings concur with the reported data by using other presynaptic cholinergic markers in AD and confirm that some degree of cholinergic degeneration, highly specific for the basal forebrain neurons, occurs in AD. However, these results, obtained in a group of AD brains belonging to severely demented patients, do not show a dramatic loss of the HACU in many AD brains. Although this fact could be due to the existence of a compensatory mechanism, our results probably suggest that dementia in AD cannot be explained only by the loss of neocortical cholinergic presynaptic terminals arising from the basal forebrain and also may clarify as to why the acetylcholine precursors or the muscarinic agonists are not effective in AD dementia.     

Evidence of angiogenic vessels in Alzheimer’s disease

Alterations in the blood brain barrier and brain vasculature may be involved in neurodegeneration and neuroinflammation. We sought to determine if vascular remodeling characterized by angiogenic vessels or increased vascular density, occurred in pathologically confirmed Alzheimer’s disease (AD) postmortem human brain tissues. We examined brains of deceased, older catholic clergy from the Religious Order Study, a longitudinal clinical–pathological study of aging and AD. The hippocampus, midfrontal cortex, substantia nigra, globus pallidus and locus ceruleus were examined for integrin αvβ3 immunoreactivity, a marker of angiogenesis, and vascular densities. Activated microglia cell counts were also performed. All areas except the globus pallidus exhibited elevated αvβ3 immunoreactivity in AD cases compared with controls. Only in the hippocampus did the ongoing angiogenesis result in increased vascular density compared with controls. Vascular density was correlated with Aβ load in the hippocampus and αvβ3 reactivity was correlated with neurofibrillary tangles in the midfrontal cortex and in the substantia nigra. These data indicate that ongoing angiogenesis is present in brain regions affected by AD pathology and may be related to tissue injury.     

Does alcohol-induced blood cell agglutination cause brain damage?

After 3 weeks of alcohol intoxication, the brains of rats were searched with light- and electron microscopy for degenerating nervous tissue and agglutination of erythrocytes in the blood vessels. There was no sign of degeneration of nerve cells or synapses in the cerebral cortex, hippocampus, cerebellum, midbrain or hindbrain. No histological sections showed blood vessels with erythrocytes inside them. It is concluded that the agglutination of red blood cells seen in the conjunctivae of intoxicated human alcoholics is not necessarily an indication that vascular congestion is also occurring in the brain of such patients, nor that this is the primary mechanism of alcohol-related brain damage.     

Declining expression of neprilysin in Alzheimer disease vasculature: possible involvement in cerebral amyloid angiopathy

Molecular, genetic, and pharmacological studies have shown that neprilysin (also called NEP) catabolizes amyloid beta peptides (A beta) in healthy conditions. However, in Alzheimer disease (AD), A beta accumulates forming senile plaques in brain parenchyma and amyloid deposition around blood vessels. In this study, we tested at cellular level the relationship between neprilysin and A beta in human healthy and AD brain. Our results provided evidence for declining levels of neprilysin in AD brains as compared to healthy controls in parallel with increasing deposition of A beta. In hippocampus of AD individuals we observed a significant down-regulation of neprilysin expression in pyramidal neurons, consistent with the possibility that neprilysin controls the level of A beta accumulation and plaque formation in this area. In the cortex and leptomeninges, neprilysin was expressed in the smooth muscle cells of blood vessels. In sections from AD patients we observed a clear inverse relationship between neprilysin and A beta peptide levels in the vasculature, implicating neprilysin in cerebral amyloid angiopathy.     

Selective cortical decrease of high-affinity choline uptake carrier in Alzheimer's disease: An autoradiographic study using3H-hemicholinium-3

Summary ³H-hemicholinium-3 (³H-HC-3) binding, a marker of the presynaptic high-affinity choline uptake carrier (HACU), was measured by autoradiography in several brain regions of 17 Alzheimer's disease (AD) patients and of 11 matched controls. A significant decrease in the density of³H-HC-3 binding sites was found in entorhinal cortex, hippocampus and layers I–III of the frontal cortex. By contrast, in the caudate-putamen the number of³H-HC-3 binding sites in AD cases was comparable to that of control striata. These data concur with previous results using classical presynaptic markers and reflect the loss in the activity of HACU, and, hence, in the synthesis of acetylcholine, that selectively occurs in cortical areas of AD brains due to the degeneration of presynaptic cholinergic terminals arising from the basal forebrain. However, the relatively low mean reduction in HACU in cortical areas (–40%), together with the apparent indemnity of this marker in certain severely demented AD cases, suggest that AD dementia cannot be explained simply by the loss of presynaptic terminals originating in the basal forebrain. These data seem to be a good explanation for the poor response to cholinergic replacement in AD.     

Increased cAMP immunostaining in cerebral vessels in Alzheimer's disease.

Increasing evidence suggests that up-regulation of the cAMP-second messenger system is implicated in Alzheimer's disease neurodegeneration. Since previous studies reported an increased level of cAMP in microvessels of Alzheimer's patients compared with those from non-demented elderly controls, we have carried out an immunohistochemical study to compare cAMP immunostaining in brain vessels from patients with dementia and neuropathological criteria of Alzheimer's disease (n=5) with those of age-matched patients (n=10). We have also included a control group of adult patients (n=5) to evaluate the role of aging separate from the effects of dementia. Our results demonstrated an increased cAMP immunostaining in cerebral cortical and meningeal vessels from Alzheimer's patients compared to nondemented elderly and adult controls. Vascular cAMP immunostaining was mainly observed in frontal and temporal cortex, the hippocampus being the region that showed the more intense and widespread vascular cAMP immunostaining. We also observed a conspicuous vascular beta-amyloid immunostaining specifically in those vessels that showed the highest cAMP immunostaining. We suggest that increased vascular cAMP immunostaining is mainly localised in the selectively vulnerable targets of neurodegeneration that characterise AD. Moreover, the co-immunolocalisation of cAMP and beta-amyloid protein in cerebral vessels of patients with AD suggests a possible role of cAMP up-regulation in the accumulation of those amyloidogenic peptides.     

Vascular dementia in leukoaraiosis may be a consequence of capillary loss not only in the lesions, but in normal-appearing white matter and cortex as well

We investigated capillary density in 12 subjects with leukoaraiosis (LA), in 9 age-matched normal subjects, in 7 cases of Alzheimer's disease (AD), and 4 after whole-brain irradiation for brain tumors. In the LA study (which as been published), autopsy brains were evaluated by MRI. The presence of LA was indicated by confluent or patchy areas of hyperintensity in the deep white matter. We employed a stereology method using computerized image processing and analysis to determine microvascular density. Afferent vessels (arterioles and capillaries, but not veins or venules) were stained for alkaline phosphatase in 100 microm thick celloidin sections. Microvascular density in LA lesions in the deep white matter (2.56%) was significantly lower than in the corresponding deep white matter of normal subjects (3.20%, p=0.0180). LA subjects demonstrated decreased vascular density at early ages (55-65 years) when compared to normal subjects. Our findings indicate that LA affects the brain globally, with capillary loss, although the parenchymal damage is found primarily in the deep white matter. In ongoing studies of the deep white matter in AD brains, we found a pattern of decreased vascular density compared to normal, as well as an age-related decline. In the four irradiated brains, we found very low vessel densities, similar to those found in LA, without an additional age-related decline.     

Expression of matrix metalloproteinase-9 and urinary-type plasminogen activator in Alzheimer's disease brain

OBJECTIVE: Urinary-type plasminogen activator (uPA) binding to uPA receptor (uPAR) promotes the activation of matrix metalloproteinase-9 (MMP-9), which degrades amyloid beta protein (Abeta) in vitro. We investigated the expression of MMP-9, uPA, and uPAR in post-mortem brains from patients with Alzheimer's disease (AD) and those with vascular dementia (VD). MATERIAL AND METHODS: We used immunohistochemistry to examine the sections of the parietal lobe and hippocampus from 4 AD and 3 VD patients. The anti-MMP-9 antibody, anti-uPA antibody, and anti-uPAR antibody were used to perform immunohistological analysis. RESULTS: In the brain tissues from the AD patients, we found expression of MMP-9 in the cytoplasm of neurons, neurofibrillary tangles, senile plaques, vascular walls and uPAR expression in the cytoplasm of neurons and vascular walls. uPA was detected only in the vascular walls. On the other hand, we could not find expression of MMP-9, uPAR and uPA in the brain tissues of the VD patients, except for the vascular walls. CONCLUSION: The neurons in the AD brains expressed MMP-9 and uPAR. MMP-9 may be produced for the degradation of Abeta, but uPA, which activates MMP-9, was not immunolocalized to the neurons in the AD brains.     

Loss of nerve growth factor receptor-containing neurons in Alzheimer's disease: a quantitative analysis across subregions of the basal forebrain

Magnocellular neurons comprising the Ch1-Ch4 regions of the basal forebrain provide topographic cholinergic innervation to the cerebral cortex, thalamus, and basolateral nucleus of the amygdala. Most quantitative studies analyzing the status of these neurons in Alzheimer's disease (AD) have employed Nissl-stained preparations. These studies principally analyzed large neurons of a prespecified cell diameter. Since basal forebrain neurons atrophy in Alzheimer's disease, an immunocytochemical marker for these neurons would appear to be a better alternative for determining whether there is regionally specific degeneration of cholinergic neurons across subregions of the basal forebrain. Brain sections from seven AD and five aged-matched control patients were immunocytochemically stained with a monoclonal antibody raised against the receptor for nerve growth factor (NGF), a probe which has previously been demonstrated to extensively and exclusively colocalize with cholinergic basal forebrain neurons in humans (17, 25, 35). NGF receptor-immunoreactive neurons within the hippocampal projecting nuclei of the medial septum (Ch1) and vertical limb of the diagonal band (Ch2) were minimally affected in AD as compared to control cases. In contrast, the Ch4 region demonstrated a significant loss of NGF receptor-immunoreactive neurons in AD that inversely correlated (-0.786) with the duration of the disease process. All four subregions of Ch4 were affected in the AD cases with the anterolateral (76.4%), intermediate (62.1%) and posterior divisions (76.5%) demonstrating the greatest reduction in NGF receptor-immunoreactive neurons. Nissl-counterstained sections failed to reveal magnocellular neurons which were not immunoreactive for the NGF receptor, suggesting that reductions in immunocytochemically stained neurons reflects neuron loss and not the failure of viable neurons to synthesize NGF receptors. These data indicate that cholinergic basal forebrain neurons which project to the amygdala, as well as to the temporal, frontobasal, and frontodorsal cortices, are most affected in AD.     

Reduced brain tissue perfusion in TGF-beta 1 transgenic mice showing Alzheimer's disease-like cerebrovascular abnormalities

We have studied the functional repercussions of cerebrovascular abnormalities in transgenic mice overexpressing TGF-beta1. These mice develop Alzheimer's disease-like vascular and meningeal alterations without parenchymal degeneration. Autoradiographic cerebral blood flow measurements in 9-month-old TGF-beta1 mice compared to non-transgenic littermates provided evidence of reduced tissue perfusion, most prominent in limbic regions. A highly significant inverse correlation was found between the density of thioflavin-S-positive blood vessels and blood flow in the hippocampus and the cortex. An inverse correlation was likewise found between meningeal staining and blood flow in thalamic nuclei and regions of high blood flow. Thus, the vascular abnormalities were associated locally with reduced perfusion rate and more widely with limitation in the blood flow. These chronic changes may be related to fibrillar and soluble A beta peptides, the amount of which was almost doubled in the brains of TGF-beta1 mice. Comparison with previous results of cerebral glucose utilization in TGF-beta1 mice shows that reduced utilization preferentially occurred in regions with a high metabolic rate and a relatively low blood flow, suggesting that the metabolic needs are not met by blood supply in these regions.     

Review: cerebral microvascular pathology in ageing and neurodegeneration

This review of age-related brain microvascular pathologies focuses on topics studied by this laboratory, including anatomy of the blood supply, tortuous vessels, venous collagenosis, capillary remnants, vascular density and microembolic brain injury. Our studies feature thick sections, large blocks embedded in celloidin, and vascular staining by alkaline phosphatase. This permits study of the vascular network in three dimensions, and the differentiation of afferent from efferent vessels. Current evidence suggests that there is decreased vascular density in ageing, Alzheimer's disease and leukoaraiosis, and cerebrovascular dysfunction precedes and accompanies cognitive dysfunction and neurodegeneration. A decline in cerebrovascular angiogenesis may inhibit recovery from hypoxia-induced capillary loss. Cerebral blood flow is inhibited by tortuous arterioles and deposition of excessive collagen in veins and venules. Misery perfusion due to capillary loss appears to occur before cell loss in leukoaraiosis, and cerebral blood flow is also reduced in the normal-appearing white matter. Hypoperfusion occurs early in Alzheimer's disease, inducing white matter lesions and correlating with dementia. In vascular dementia, cholinergic reductions are correlated with cognitive impairment, and cholinesterase inhibitors have some benefit. Most lipid microemboli from cardiac surgery pass through the brain in a few days, but some remain for weeks. They can cause what appears to be a type of vascular dementia years after surgery. Donepezil has shown some benefit. Emboli, such as clots, cholesterol crystals and microspheres can be extruded through the walls of cerebral vessels, but there is no evidence yet that lipid emboli undergo such extravasation.     

Expression of leukocyte antigen CD34 by brain capillaries in Alzheimer's disease and neurologically normal subjects

Summary We studied the expression of a hemopoietic progenitor cell antigen, designated CD34, in brains from subjects with Alzheimer's disease (AD) and nonneurological controls. Immunoblots of brain microvessel proteins probed with monoclonal antibody QBEND/10 to the leukocyte antigen CD34 recognized a protein band with an apparent molecular mass of 90–100 kDa. Immunocytochemical staining of brain tissue sections showed CD34 to be expressed by all microvasculature including those of the circumventricular organs. In normal control brains such specific staining exhibited by QBEND/10 was indistinguishable from that obtained with collagen IV antibodies. In AD, however, increased vascular tendrils in form of endothelial abluminal processes and intraparenchymal abnormalities were evident in cortical and hippocampal regions, predominant in cases with severe pathology. Our results demonstrate that the leukocyte antigen CD34 is localized with the vascular endothelium throughout the human brain. These results also suggest that CD34 detects endothelial abnormalities in brains of AD subjects and support previous observations on the usefulness of CD34 to label abluminal microprocesses.Supported in part by a grant from the National Alzheimer's Disease Association (ADRA) and USPHS grant AG 08012.     

Morphological Changes of Blood Vessels in the Brain with Alzheimer's Disease

Abstract: Morphological changes of microvessels in the cerebral cortices of Alzheimer's disease and control brains were examined. From several parts of the brains, all of the vessels in blocks of tissues were isolated with ultrasound treatment and mesh filtration, and were observed by light microscopy. The results obtained were as follows: There was no difference between the relatively large arteries of the brains with Alzheimer's disease and the control brains. However, in the Alzheimer's brain irregular shapes of blood vessels and degenerated smooth muscle cells of a single layer were observed in the terminal arterioles. In the capillaries, focal constrictions and irregular shapes were observed. In addition to these changes, the nuclei of endothelial cells were irregular and unclear. These findings seem to indicate that the degeneration of microvessels in the brain of Alzheimer's disease might have occurred at the terminal arterioles and the capillaries.     

Brain-reactive autoantibodies prevalent in human sera increase intraneuronal amyloid-β(1-42) deposition

Previous studies have reported immunoglobulin-positive neurons in Alzheimer's disease (AD) brains, an observation indicative of blood-brain barrier (BBB) breakdown. Recently, we demonstrated the nearly ubiquitous presence of brain-reactive autoantibodies in human sera. The significance of these observations to AD pathology is unknown. Here, we show that IgG-immunopositive neurons are abundant in brain regions exhibiting AD pathology, including intraneuronal amyloid-β(42) (Aβ(42)) and amyloid plaques, and confirm by western analysis that brain-reactive autoantibodies are nearly ubiquitous in human serum. To investigate a possible interrelationship between neuronal antibody binding and Aβ pathology, we tested the effects of human serum autoantibodies on the intraneuronal deposition of soluble Aβ(42) peptide in adult mouse neurons in vitro (organotypic brain slice cultures). Binding of human autoantibodies to mouse neurons dramatically increased the rate and extent of intraneuronal Aβ(42) accumulation in the mouse cerebral cortex and hippocampus. Additionally, individual sera exhibited variable potency related to their capacity to enhance intraneuronal Aβ(42) peptide accumulation and immunolabel neurons in AD brain sections. Replacement of human sera with antibodies targeting abundant neuronal surface proteins resulted in a comparable enhancement of Aβ(42) accumulation in mouse neurons. Overall, results suggest that brain-reactive autoantibodies are ubiquitous in the blood and that a defective BBB allows these antibodies to access the brain interstitium, bind to neuronal surfaces and enhance intraneuronal deposition of Aβ(42) in AD brains. Thus, in the context of BBB compromise, brain-reactive autoantibodies may be an important risk factor for the initiation and/or progression of AD as well as other neurodegenerative diseases.     

APOE epsilon 4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of A beta protein

The relative amounts of amyloid beta-protein (A beta) in cerebral blood vessels and parenchyma vary considerably amongst patients with Alzheimer's disease (AD). Although several mechanisms have been proposed to explain this variability, the underlying genetic and environmental determinants are still unclear, as are the functional consequences. Polymorphisms in APOE, the gene for apolipoprotein E (ApoE), influence the risk of developing AD and of deposition of A beta within the brain. We examined the relationship between the APOE genotype and the relative extent of accumulation of A beta as plaques within the cerebral parenchyma and in cortical blood vessels in the form of cerebral amyloid angiopathy (CAA), in autopsy brain tissue from 125 AD cases and from 53 elderly, neurologically normal controls of which 19 had CAA without other neuropathological features of AD. In the AD cases, we also assessed whether the severity of CAA was related to the age of onset and duration of dementia, risk factors for atherosclerotic vascular disease, and histologically demonstrable cerebral infarcts or foci of haemorrhage. The APOE genotype was determined by a standard polymerase chain reaction-based method. Paraffin sections of frontal, temporal and parietal lobes were immunolabelled for A beta and the parenchymal A beta load (total A beta minus vessel-associated A beta) was quantified by computer-assisted image analysis. CAA severity was scored for cortical and leptomeningeal vessels. The relevant clinical data were obtained from the database of the South West Brain Bank. In AD, we found the severity of CAA to be strongly associated with the number of epsilon 4 alleles (P < 0.0001) but the parenchymal A beta load to be independent of APOE genotype. Cases with severe CAA had a lower parenchymal A beta load than had those with moderate CAA (P = 0.003). Neither the severity of CAA nor the parenchymal A beta load correlated with age of onset, duration of disease or age at death, and the severity of CAA also did not correlate with the presence of cerebral infarcts or foci of haemorrhage. These findings indicate that possession of the APOE epsilon 4 allele favours vascular over parenchymal accumulation of A beta in AD. This may influence the pathogenesis of neurodegeneration in epsilon 4-associated AD.     

Changes in cerebral blood volume and amyloid pathology in aged Alzheimer APP/PS1 mice on a docosahexaenoic acid (DHA) diet or cholesterol enriched Typical Western Diet (TWD)

High dietary cholesterol and low dietary docosahexaenoic acid (DHA) intake are risk factors for Alzheimer's disease (AD). However, it is unclear how these components influence the course of the disease. We investigated the effects of dietary lipids on beta-amyloid deposition and blood circulation in the brains of 18-month-old APP/PS1 mice. Starting at 6 months of age, mice were fed a regular rodent chow, a Typical Western Diet (TWD) containing 1% cholesterol, or a diet with a high (0.5%) level of DHA for 12 months. Relative cerebral blood volume (rCBV) and flow (CBF) were determined with (2)H MR spectroscopy and gradient echo contrast enhanced MRI. Deposition of beta-amyloid was visualized in fixed brain tissue with immunohistochemistry. The TWD diet increased plaque burden in the dentate gyrus of the hippocampus, but did not significantly reduce rCBV. In contrast, the DHA-enriched diet increased rCBV without changing blood flow indicating a larger circulation in the brain probably due to vasodilatation and decreased the amount of vascular beta-amyloid deposition. Together, our results indicate that the long-term intake of dietary lipids can impact both brain circulation and beta-amyloid deposition, and support the involvement of hemodynamic changes in the development of AD.     

Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy

The deposition of amyloid-β (Aβ) peptides in the walls of leptomeningeal and cortical blood vessels as cerebral amyloid angiopathy (CAA) is present in normal ageing and the majority of Alzheimer’s disease (AD) brains. The failure of clearance mechanisms to eliminate Aβ from the brain contributes to the development of sporadic CAA and AD. Here, we investigated the effects of CAA and ageing on the pattern of perivascular drainage of solutes in the brains of naïve mice and in the Tg2576 mouse model of AD. We report that drainage of small molecular weight dextran along cerebrovascular basement membranes is impaired in the hippocampal capillaries and arteries of 22-month-old wild-type mice compared to 3- and 7-month-old animals, which was associated with age-dependent changes in capillary density. Age-related alterations in the levels of laminin, fibronectin and perlecan in vascular basement membranes were also noted in wild-type mice. Furthermore, dextran was observed in the walls of veins of Tg2576 mice in the presence of CAA, suggesting that deposition of Aβ in vessel walls disrupts the normal route of elimination of solutes from the brain parenchyma. These data support the hypothesis that perivascular solute drainage from the brain is altered both in the ageing brain and as a consequence of CAA. These findings have implications for the success of therapeutic strategies for the treatment of AD that rely upon the health of the ageing cerebral vasculature.     

α7 nicotinic acetylcholine receptor expression in Alzheimer's disease

The brains of people with Alzheimer's disease (AD) display several characteristic pathological features, including deposits (plaques) of beta-amyloid 1-42 (Abeta1-42), intraneuronal accumulations (tangles) of hyperphosphorylated tau, degeneration of the basal forebrain cholinergic pathway, and gliosis. Abeta1-42 plaques develop in specific brain regions, including hippocampus and cortex, as well as in the vasculature. Abeta1-42 might promote neurodegeneration through the induction of free radicals and disruption of Ca2+ homeostasis, giving rise to the symptoms of AD. Abeta1-42 interacts with the alpha7 subtype of the nicotinic acetylcholine receptor (alpha7 nAChR), which is widely expressed throughout the central and peripheral nervous systems, as well as in several nonneuronal loci, such as epithelial cells, lymphoid tissues, and peripheral blood lymphocytes. Western blot and autoradiographic analyses indicate that the alpha7 nAChR subunit protein is up-regulated in human brain samples from Alzheimer patients, as well as in animal models of AD (Dineley et al., 2001; Bednar et al., 2002), and might be involved in nicotine-mediated reduction of Abeta1-42 deposition (Hellstrom et al., 2004), although the nature of this relationship remains ill-defined. We have undertaken a semiquantitative histological evaluation of alpha7 nAChR expression in a mouse model of AD pathology, as well as a comparison of alpha7 nAChR levels in lymphocytes from AD patients and control subjects.