Consequence of Aβ immunization on the vasculature of human Alzheimer's disease brain (original) (raw)
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Consequence of A immunization on the vasculature of human Alzheimer's disease brain
Brain, 2008
A major feature of Alzheimer's disease is the accumulation of amyloid-b peptide (Ab) in the brain both in the form of plaques in the cerebral cortex and in blood vessel as cerebral amyloid angiopathy (CAA). Experimental models and human clinical trials have shown that accumulation of Ab plaques can be reversed by immunotherapy. In this study, we hypothesized that Ab in plaques is solubilized by antibodies generated by immunization and drains via the perivascular pathway, detectable as an increase in cerebrovascular Ab. We have performed a follow up study of Alzheimer's disease patients immunized against Ab42. Neuropathological examination was performed on nine patients who died between four months and five years after their first immunization. Immunostaining for Ab40 and Ab42 was quantified and compared with that in unimmunized Alzheimer's disease controls (n = 11). Overall, compared with these controls, the group of immunized patients had approximately 14 times as many blood vessels containing Ab42 in the cerebral cortex (P_0.001) and seven times more in the leptomeninges (P = 0.013); among the affected blood vessels in the immunized cases, most of them had full thickness and full circumference involvement of the vessel wall in the cortex (P = 0.001), and in the leptomeninges (P = 0.015). There was also a significantly higher level of cerebrovascular Ab40 in the immunized cases than in the unimmunized cases (cortex: P = 0.009 and leptomeninges: P = 0.002). In addition, the immunized patients showed a higher density of cortical microhaemorrhages and microvascular lesions than the unimmunized controls, though none had major CAA-related intracerebral haemorrhages. The changes in cerebral vascular Ab load did not appear to substantially influence the structural proteins of the blood vessels. Unlike most of the immunized patients, two of the longest survivors, four to five years after first immunization, had virtually complete absence of both plaques and CAA, raising the possibility that, given time, Ab is eventually cleared from the cerebral vasculature. The findings are consistent with the hypothesis that Ab immunization results in solubilization of plaque Ab42 which, at least in part, exits the brain via the perivascular pathway, causing a transient increase in the severity of CAA. The extent to which these vascular alterations following Ab immunization in Alzheimer's disease are reflected in changes in cognitive function remains to be determined.
Amyloid-β Peptide Remnants in AN-1792-Immunized Alzheimer's Disease Patients
The American Journal of Pathology, 2006
Experiments with amyloid- (A)-42-immunized transgenic mouse models of Alzheimer's disease have revealed amyloid plaque disruption and apparent cognitive function recovery. Neuropathological examination of patients vaccinated against purified A-42 (AN-1792) has demonstrated that senile plaque disruption occurred in immunized humans as well. Here, we examined tissue histology and quantified and biochemically characterized the remnant amyloid peptides in the gray and white matter and leptomeningeal/cortical vessels of two AN-1792-vaccinated patients, one of whom developed meningoencephalitis. Compact core and diffuse amyloid deposits in both vaccinated individuals were focally absent in some regions. Although parenchymal amyloid was focally disaggregated, vascular deposits were relatively preserved or even increased. Immunoassay revealed that total soluble amyloid levels were sharply elevated in vaccinated patient gray and white matter compared with Alzheimer's disease cases. Our exper-iments suggest that although immunization disrupted amyloid deposits, vascular capture prevented largescale egress of A peptides. Trapped, solubilized amyloid peptides may ultimately have cascading toxic effects on cerebrovascular, gray and white matter tissues. Anti-amyloid immunization may be most effective not as therapeutic or mitigating measures but as a prophylactic measure when A deposition is still minimal. This may allow A mobilization under conditions in which drainage and degradation of these toxic peptides is efficient.
The Pathology of Alzheimer Disease Elicits an In Vivo Immunological Response
American Journal of Immunology, 2007
The mechanism(s) responsible for the loss of neurons that characterizes Alzheimer disease is incompletely understood. Nonetheless, there is considerable evidence suggestive of immune abnormalities coupled to alterations in blood-brain barrier permeability that likely play a key role in both the etiology and progression of the disease. To examine these issues further, this study was designed to examine the presence of human antibodies within hippocampal regions of both diseased and normal brains. Specifically, using antibodies directed against either human lambda () or kappa () subunits of human IgG, we examined the amount and localization of endogenous human antibodies within the brain. In cases of Alzheimer disease, but not in age-matched controls, we found human antibodies associated with pyramidal neurons and dystrophic neurites surrounding amyloid plaquespathological structures that characterize the disease. Since such human immunoglobulins likely originate in the vasculature, we also examined cases of cerebral amyloid angiopathy to further explore the importance of blood-brain barrier breaches and found high levels of antibodies associated with many blood vessels as well as pyramidal neurons. Taken together, these findings strengthen the notion that alterations in blood brain barrier permeability in both Alzheimer disease and cerebral amyloid angiopathy leads to the accumulation of antibodies that then may contribute to the inflammatory cascade within the brain.
Aβ immunotherapy for Alzheimer's disease: effects on apoE and cerebral vasculopathy
Acta neuropathologica, 2014
Aβ immunotherapy for Alzheimer's disease (AD) results in the removal of Aβ plaques and increased cerebral amyloid angiopathy (CAA). In current clinical trials, amyloid-related imaging abnormalities (ARIAs), putatively due to exacerbation of CAA, are concerning side effects. We aimed to assess the role of the Aβ transporter apolipoprotein E (apoE) in the exacerbation of CAA and development of CAA-associated vasculopathy after Aβ immunotherapy. 12 Aβ42-immunized AD (iAD; AN1792, Elan Pharmaceuticals) cases were compared with 28 unimmunized AD (cAD) cases. Immunohistochemistry was quantified for Aβ42, apoE, apoE E4 and smooth muscle actin, and CAA-associated vasculopathy was analyzed. Aβ immunotherapy was associated with redistribution of apoE from cortical plaques to cerebral vessel walls, mirroring the altered distribution of Aβ42. Concentric vessel wall splitting was increased threefold in leptomeningeal vessels after immunotherapy (cAD 6.3 vs iAD 20.6 %, P < 0.001), but smoo...
European Journal of Neuroscience, 2006
Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. The meningoencephalitis observed in the first AD vaccination trial was likely related to excessive cell-mediated immunity caused by the immunogen, amyloid-β (Aβ) 1-42, and the adjuvant, QS-21. To avoid this toxicity, we have been using Aβ derivatives in alum adjuvant that promotes humoral immunity. Other potential side effects of immunotherapy are increased vascular amyloid and associated microhemorrhages that may be related to rapid clearance of parenchymal amyloid. Here, we determined if our immunization strategy was associated with this form of toxicity, and if the therapeutic effect was age-dependent. Tg2576 mice and wild-type littermates were immunized from 11 or 19 months and their behaviour evaluated prior to killing at 24 months. Subsequently, plaque-and vascular-Aβ burden, Aβ levels and associated pathology was assessed. The therapy started at the cusp of amyloidosis reduced cortical Aβ deposit burden by 31% and Aβ levels by 30-37%, which was associated with cognitive improvements. In contrast, treatment from 19 months, when pathology is well established, was not immunogenic and therefore did not reduce Aβ burden or improve cognition. Significantly, the immunotherapy in the 11-24 months treatment group, that reduced Aβ burden, did not increase cerebral bleeding or vascular Aβ deposits in contrast to several Aβ antibody studies. These findings indicate that our approach age-dependently improves cognition and reduces Aβ burden when used with an adjuvant suitable for humans, without increasing vascular Aβ deposits or microhemorrhages.
Acta Neuropathologica, 2009
The introduction of immunotherapy and its ultimate success will require re-evaluation of the pathogenesis of Alzheimer's disease particularly with regard to the role of the ageing microvasculature and the eVects of APOE genotype. Arteries in the brain have two major functions (a) delivery of blood and (b) elimination of interstitial Xuid and solutes, including amyloid-(A), along perivascular pathways (lymphatic drainage). Both these functions fail with age and particularly severely in Alzheimer's disease and vascular dementia. Accumulation of A as plaques in brain parenchyma and artery walls as cerebral amyloid angiopathy (CAA) is associated with failure of perivascular elimination of A from the brain in the elderly and in Alzheimer's disease. High levels of soluble A in the brain correlate with cognitive decline in Alzheimer's disease and reXect the failure of perivascular drainage of solutes from the brain and loss of homeostasis of the neuronal environment. Clinically and pathologically, there is a spectrum of disease related to functional failure of the ageing microvasculature with "pure" Alzheimer's disease at one end of the spectrum and vascular dementia at the other end. Changes in the cerebral microvasculature with age have a potential impact on therapy with cholinesterase inhibitors and especially on immunotherapy that removes A from plaques in the brain, but results in an increase in severity of CAA and no clear improvement in cognition. Drainage of A along perivascular pathways in ageing artery walls may need to be improved to maximise the potential for improvement of cognitive function with immunotherapy. Keywords Structure and functions of normal cerebral arteries • Perivascular drainage of A • Cerebral amyloid angiopathy • Microvascular disease • Arteriosclerosis • Arteriolosclerosis • Vascular dementia • Alzheimer's disease • Brain homeostasis • Cholinesterase inhibitors • Immunotherapy