W E Van Nostrand

Review: Sporadic cerebral amyloid angiopathy

J. Attems, K. Jellinger, D. R. Thal and W. Van Nostrand (2011) Neuropathology and Applied Neurobiology37, 75–93
Sporadic cerebral amyloid angiopathy

NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease

Alzheimers disease is characterized by two primary pathological features: amyloid plaques and neurofibrillary tangles. The interconnection between amyloid and tau aggregates is of intense interest, but mouse models have yet to reveal a direct interrelationship. We now show that NO may be a key factor that connects amyloid and tau pathologies. Genetic removal of NO synthase 2 in mice expressing mutated amyloid precursor protein results in pathological hyperphosphorylation of mouse tau, its redistribution to the somatodendritic compartment in cortical and hippocampal neurons, and aggregate formation. Lack of NO synthase 2 in the amyloid precursor protein Swedish mutant mouse increased insoluble β-amyloid peptide levels, neuronal degeneration, caspase-3 activation, and tau cleavage, suggesting that NO acts at a junction point between β-amyloid peptides, caspase activation, and tau aggregation.

Metallothionein-I and -III expression in animal models of alzheimer disease

Previous studies have described altered expression of metallothioneins (MTs) in neurodegenerative diseases like multiple sclerosis (MS), Down syndrome, and Alzheimers disease (AD). In order to gain insight into the possible role of MTs in neurodegenerative processes and especially in human diseases, the use of animal models is a valuable tool. Several transgenic mouse models of AD amyloid deposits are currently available. These models express human beta-amyloid precursor protein (AbetaPP) carrying different mutations that subsequently result in a varied pattern of beta-amyloid (Abeta) deposition within the brain. We have evaluated the expression of MT-I and MT-III mRNA by in situ hybridization in three different transgenic mice models of AD: Tg2576 (carrying AbetaPP harboring the Swedish K670N/M671L mutations), TgCRND8 (Swedish and the Indiana V717F mutations), and Tg-SwDI (Swedish and Dutch/Iowa E693Q/D694N mutations). MT-I mRNA levels were induced in all transgenic lines studied, although the pattern of induction differed between the models. In the Tg2576 mice MT-I was weakly upregulated in cells surrounding Congo Red-positive plaques in the cortex and hippocampus. A more potent induction of MT-I was observed in the cortex and hippocampus of the TgCRND8 mice, likely reflecting their higher amyloid plaques content. MT-I upregulation was also more significant in Tg-SwDI mice, especially in the subiculum and hippocampus CA1 area. Immunofluorescence stainings demonstrate that astrocytes and microglia/macrophages surrounding the plaques express MT-I&II. In general, MT-I regulation follows a similar but less potent response than glial fibrillary acidic protein (GFAP) expression. In contrast to MT-I, MT-III mRNA expression was not significantly altered in any of the models examined suggesting that the various MT isoforms may have different roles in these experimental systems, and perhaps also in human AD.

APOE-Mimetic Peptides Reduce Behavioral Deficits, Plaques and Tangles in Alzheimer's Disease Transgenics

Background: After age, the second largest risk factor for Alzheimer’s disease (AD) is apolipoprotein E (APOE) genotype, where APOE4 is associated with lower apoE protein levels, more severer brain pathology, enhanced inflammation and disease. Small peptides corresponding to the receptor-binding region of apoE mimic the anti-inflammatory activity of the apoE holoprotein. These apoE mimetics greatly improve behavioral outcomes and neuronal survival in head trauma models that display AD pathology and neuronal loss. Objective: To determine whether apoE mimetics change behavior, inflammation and pathology in CVND-AD (SwDI-APP/NOS2–/–) transgenic mice. Methods: Starting at 9 months, apoE peptides were subcutaneously administered 3 times per week for 3 months followed by behavioral, histochemical and biochemical testing. Results: Treatment with apoE mimetics significantly improved behavior while decreasing the inflammatory cytokine IL-6, neurofibrillary tangle-like and amyloid plaque-like structures. Biochemical measures matched the visible pathological results. Conclusions: Treatment with apoE mimetics significantly improved behavior, reduced inflammation and reduced pathology in CVND-AD mice. These improvements are associated with apoE-mimetic-mediated increases in protein phosphatase 2A activity. Testing in additional AD models showed similar benefits, reinforcing this novel mechanism of action of apoE mimetics. These data suggest that the combination of anti-inflammatory and neuroprotective activities of apoE mimetics represents a new generation of potential therapeutics for AD.

Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry

Abstract In the 12 years since the publication of the first Consensus Paper of the WFSBP on biomarkers of neurodegenerative dementias, enormous advancement has taken place in the field, and the Task Force takes now the opportunity to extend and update the original paper. New concepts of Alzheimer’s disease (AD) and the conceptual interactions between AD and dementia due to AD were developed, resulting in two sets for diagnostic/research criteria. Procedures for pre-analytical sample handling, biobanking, analyses and post-analytical interpretation of the results were intensively studied and optimised. A global quality control project was introduced to evaluate and monitor the inter-centre variability in measurements with the goal of harmonisation of results. Contexts of use and how to approach candidate biomarkers in biological specimens other than cerebrospinal fluid (CSF), e.g. blood, were precisely defined. Important development was achieved in neuroimaging techniques, including studies comparing amyloid-β positron emission tomography results to fluid-based modalities. Similarly, development in research laboratory technologies, such as ultra-sensitive methods, raises our hopes to further improve analytical and diagnostic accuracy of classic and novel candidate biomarkers. Synergistically, advancement in clinical trials of anti-dementia therapies energises and motivates the efforts to find and optimise the most reliable early diagnostic modalities. Finally, the first studies were published addressing the potential of cost-effectiveness of the biomarkers-based diagnosis of neurodegenerative disorders.

Sporadic cerebral amyloid angiopathy

J. Attems, K. Jellinger, D. R. Thal and W. Van Nostrand (2011) Neuropathology and Applied Neurobiology37, 75–93
Sporadic cerebral amyloid angiopathy

Clearance of Amyloid-β Protein Deposits in Transgenic Mice following Focal Cerebral Ischemia

Background/Aims: There is increased amyloid-β protein precursor (AβPP) expression and amyloid-β protein (Aβ) production in the brain shortly following cerebral ischemic stroke in rodent models. It has been postulated that this may seed amyloid deposition in the brain. On the other hand, it remains unclear how cerebral ischemia affects preexisting Aβ deposits in the brain. Here we determine the consequences of focal ischemic stroke on existing Aβ pathology in Tg-SwDI transgenic mice. Methods: At 12 months of age, Tg-SwDI mice were subjected to photo-induced focal cerebral ischemia in one hemisphere. One, 7, or 21 days after lesioning, the amount of deposited Aβ in the ischemic and control hemispheres was measured using ELISA. Image analysis was used to visualize deposited Aβ and the presence of microglia/macrophages. Results: After 7 days, and further after 21 days, there was a dramatic reduction in the amount of deposited Aβ and increased presence of microglia/macrophages in the ischemic hemisphere of the mice. Conclusions: Focal cerebral ischemia leads to clearance of deposited Aβ in Tg-SwDI mice starting at 7 days with almost complete removal in the ischemic area by 21 days. The delayed clearance of Aβ following focal cerebral ischemia may involve the infiltration of activated neuroinflammatory cells.

Early-onset subicular microvascular amyloid and neuroinflammation correlate with behavioral deficits in vasculotropic mutant amyloid β-protein precursor transgenic mice

Cerebral microvascular amyloid beta protein (Abeta) deposition and associated neuroinflammation are increasingly recognized as an important component leading to cognitive impairment in Alzheimers disease and related cerebral amyloid angiopathy (CAA) disorders. Transgenic mice expressing the vasculotropic Dutch/Iowa (E693Q/D694N) mutant human Abeta precursor protein in brain (Tg-SwDI) accumulate abundant cerebral microvascular fibrillar amyloid deposits exhibiting robust neuroinflammation. In the present study, we sought to determine if the unique amyloid pathology of Tg-SwDI mice was associated with deficits in behavioral performance. Behavioral performance tests that assessed a variety of psychological functions, including overall activity, motor ability, balance and strength, anxiety, impulsivity, and learning were conducted on homozygous Tg-SwDI mice and similarly aged wild-type C57Bl/6 mice. Our results indicate that Tg-SwDI mice were impaired in the performance of the Barnes maze learning and memory task at 3, 9, and 12 months of age. While more widespread cerebral microvascular Abeta pathology was evident in older animals, the evaluation of the Abeta pathology in the 3 months old transgenic animals revealed specific accumulation of microvascular amyloid and markedly elevated numbers of reactive astrocytes and activated microglia restricted to the subiculum. These findings indicate that early-onset accumulation of subicular microvascular amyloid and accompanying neuroinflammation correlates with impaired performance in the learning and memory task in Tg-SwDI mice.

Animal models of cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA), due to vascular amyloid β (Aβ) deposition, is a risk factor for intracerebral haemorrhage and dementia. CAA can occur in sporadic or rare hereditary forms, and is almost invariably associated with Alzheimers disease (AD). Experimental (animal) models are of great interest in studying mechanisms and potential treatments for CAA. Naturally occurring animal models of CAA exist, including cats, dogs and non-human primates, which can be used for longitudinal studies. However, due to ethical considerations and low throughput of these models, other animal models are more favourable for research. In the past two decades, a variety of transgenic mouse models expressing the human Aβ precursor protein (APP) has been developed. Many of these mouse models develop CAA in addition to senile plaques, whereas some of these models were generated specifically to study CAA. In addition, other animal models make use of a second stimulus, such as hypoperfusion or hyperhomocysteinemia (HHcy), to accelerate CAA. In this manuscript, we provide a comprehensive review of existing animal models for CAA, which can aid in understanding the pathophysiology of CAA and explore the response to potential therapies.

Review: Sporadic cerebral amyloid angiopathy: Cerebral amyloid angiopathy

J. Attems, K. Jellinger, D. R. Thal and W. Van Nostrand (2011) Neuropathology and Applied Neurobiology37, 75–93
Sporadic cerebral amyloid angiopathy