Abstract
The characteristic neuropathological changes associated with Alzheimer’s disease (AD) and other lines of evidence support the amyloid cascade hypothesis. Viewing amyloid deposits as the prime instigator of dementia has now led to clinical trials of multiple strategies to remove or prevent their formation. We performed neuropathological and biochemical assessments of 3 subjects treated with bapineuzumab infusions. Histological analyses were conducted to quantify amyloid plaque densities, Braak stages and the extent of cerebral amyloid angiopathy (CAA). Amyloid-β (Aβ) species in frontal and temporal lobe samples were quantified by ELISA. Western blots of amyloid-β precursor protein (AβPP) and its C-terminal (CT) fragments as well as tau species were performed. Bapineuzumab-treated (Bapi-AD) subjects were compared to non-immunized age-matched subjects with AD (NI-AD) and non-demented control (NDC) cases. Our study revealed that Bapi-AD subjects exhibited overall amyloid plaque densities similar to those of NI-AD cases. In addition, CAA was moderate to severe in NI-AD and Bapi-AD patients. Although histologically-demonstrable leptomeningeal, cerebrovascular and neuroparenchymal-amyloid densities all appeared unaffected by treatment, Aβ peptide profiles were significantly altered in Bapi-AD subjects. There was a trend for reduction in total Aβ42 levels as well as an increase in Aβ40 which led to a corresponding significant decrease in Aβ42:Aβ40 ratio in comparison to NI-AD subjects. There were no differences in the levels of AβPP, CT99 and CT83 or tau species between Bapi-AD and NI-AD subjects. The remarkable alteration in Aβ profiles reveals a dynamic amyloid production in which removal and depositional processes were apparently perturbed by bapineuzumab therapy. Despite the alteration in biochemical composition, all 3 immunized subjects exhibited continued cognitive decline.
Highlights
The most common form of dementia is Alzheimer’s disease (AD), currently affecting about 24 million people worldwide with expected doubling of incidence every 20 years [1]
The average brain weight of the Bapi-AD individuals was 1101 g which was very close to the average weight of the nonimmunized age-matched subjects with AD (NI-AD) cases (1059 g), suggestive of some degree of atrophy when compared to the mean weight of the non-demented control (NDC) group (1281 g)
There was a wide variation in cerebral amyloid angiopathy (CAA) content (Table 1): none to mild in NDC, none to mild in NI-AD and moderate to severe in the case of the Bapi-AD
Summary
The most common form of dementia is Alzheimer’s disease (AD), currently affecting about 24 million people worldwide with expected doubling of incidence every 20 years [1]. The disease is neuropathologically characterized by the profuse deposition of fibrillar amyloid-b (Ab) peptides, amyloid plaques (AP) and cerebral amyloid angiopathy (CAA) as well as the intraneuronal accumulation of neurofibrillary tangles (NFT) mainly composed of tau protein. The abundance of these lesions has lent support to the amyloid cascade hypothesis as the fundamental causative incident in the pathogenesis of AD. This model has been reinforced by the fact that AP, CAA and NFT are present in familial AD (FAD) due to presenilin (PS) and amyloid-b precursor protein (AbPP) mutations and are recapitulated in genetically-engineered transgenic (Tg) mice bearing mutated forms of AbPP, PS and tau. Passive and active immunotherapies have been effective in the removal of Ab in AbPP and PS Tg mice models, the application of these interventions to AD patients has been only partially successful from a neuropathological perspective [5,6,7,8,9], while no clear beneficial modification of the disease course has been observed in clinical trials [7,10,11]
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