The Arctic AßPP mutation leads to Alzheimer's disease pathology with highly variable topographic deposition of differentially truncated Aß.

BACKGROUND: The Arctic mutation (p.E693G/p.E22G)fs within the ß-amyloid (Aß) region of the ß-amyloid precursor protein gene causes an autosomal dominant disease with clinical picture of typical Alzheimer's disease. Here we report the special character of Arctic AD neuropathology in four deceased patients. RESULTS: Aß deposition in the brains was wide-spread (Thal phase 5) and profuse. Virtually all parenchymal deposits were composed of non-fibrillar, Congo red negative Aß aggregates. Congo red only stained angiopathic vessels. Mass spectrometric analyses showed that Aß deposits contained variably truncated and modified wild type and mutated Aß species. In three of four Arctic AD brains, most cerebral cortical plaques appeared targetoid with centres containing C-terminally (beyond aa 40) and variably N-terminally truncated Aß surrounded by coronas immunopositive for Aßx-42. In the fourth patient plaque centres contained almost no Aß making the plaques ring-shaped. The architectural pattern of plaques also varied between different anatomic regions. Tau pathology corresponded to Braak stage VI, and appeared mainly as delicate neuropil threads (NT) enriched within Aß plaques. Dystrophic neurites were scarce, while neurofibrillary tangles were relatively common. Neuronal perikarya within the Aß plaques appeared relatively intact. CONCLUSIONS: In Arctic AD brain differentially truncated abundant Aß is deposited in plaques of variable numbers and shapes in different regions of the brain (including exceptional targetoid plaques in neocortex). The extracellular non-fibrillar Aß does not seem to cause overt damage to adjacent neurons or to induce formation of neurofibrillary tangles, supporting the view that intracellular Aß oligomers are more neurotoxic than extracellular Aß deposits. However, the enrichment of NTs within plaques suggests some degree of intra-plaque axonal damage including accumulation of hp-tau, which may impair axoplasmic transport, and thereby contribute to synaptic loss. Finally, similarly as the cotton wool plaques in AD resulting from exon 9 deletion in the presenilin-1 gene, the Arctic plaques induced only modest glial and inflammatory tissue reaction.

Specific uptake of an amyloid-ß protofibril-binding antibody-tracer in AßPP transgenic mouse brain.

Evidence suggests that amyloid-ß (Aß) protofibrils/oligomers are pathogenic agents in Alzheimer's disease (AD). Unfortunately, techniques enabling quantitative estimates of these species in patients or patient samples are still rather limited. Here we describe the in vitro and ex vivo characteristics of a new antibody-based radioactive ligand, [125I]mAb158, which binds to Aß protofibrils with high affinity. [125I]mAb158 was specifically taken up in brain of transgenic mice expressing amyloid-ß protein precursor (AßPP) as shown ex vivo. This was in contrast to [125I]mAb-Ly128 which does not bind to Aß. The uptake of intraperitoneally-administered [125I]mAb158 into the brain was age- and time-dependent, and saturable in AßPP transgenic mice with modest Aß deposition. Brain uptake was also found in young AßPP transgenic mice that were devoid of Aß deposits, suggesting that [125I]mAb158 targets soluble Aß protofibrils. The radioligand was diffusely located in the parenchyma, sometimes around senile plaques and only occasionally colocalized with cerebral amyloid angiopathy. A refined iodine-124-labeled version of mAb158 with much improved blood-brain barrier passage and a shorter plasma half-life might be useful for PET imaging of Aß protofibrils.

The Arctic amyloid-ß precursor protein (AßPP) mutation results in distinct plaques and accumulation of N- and C-truncated Aß.

The Arctic (p. E693G) mutation in the amyloid-ß precursor protein (AßPP) facilitates amyloid-ß (Aß) protofibril formation and generates clinical symptoms of Alzheimer's disease (AD). Here, molecular details of Aß in post mortem brain were investigated with biochemical and morphological techniques. The basic structure of Arctic plaques resembled cotton wool plaques. However, they appeared ring-formed with Aß42-specific antibodies, but were actually targetoid, since the periphery and center of many parenchymal Aß deposits stained differently with mid-domain, N- and C-terminal Aß antibodies. Aß fibrils were similar in shape, albeit shorter than in sporadic AD brain, when examined by electron microscopy. Aßwild-type and Aßarctic codeposited and parenchymal deposits were highly enriched in both N- and C-terminally truncated Aß. In contrast, cerebral amyloid angiopathy (CAA) contained a substantial amount of Aß1-40. The absence of plaques with cores of fibrillary Aß might be due to the scarcity of full-length Aß, although other mechanisms could be involved. Our findings are discussed in relation to mechanisms and relevance of amyloid formation and to the clinical features of AD.

Observations in APP bitransgenic mice suggest that diffuse and compact plaques form via independent processes in Alzheimer's disease.

Studies of familial Alzheimer's disease suggest that misfolding and aggregation of amyloid-ß (Aß) peptides initiate the pathogenesis. The Arctic mutation of Aß precursor protein (APP) results in AD, and Arctic Aß is more prone to form Aß protofibrils and extracellular deposits. Herein is demonstrated that the burden of diffuse Aß deposits but not compact plaques is increased when tg-Swe mice are crossed with tg-ArcSwe mice synthesizing low levels of Arctic Aß. The diffuse deposits in bitransgenic mice, which contain primarily wild-type Aß42, accumulate in regions both with and without transgene expression. However, APP processing, when compared with tg-Swe, remains unchanged in young bitransgenic mice, whereas wild-type Aß42 aggregation is accelerated and fibril architecture is altered in vitro and in vivo when a low level of Arctic Aß42 is introduced. Thus, the increased number of diffuse deposits is likely due to physical interactions between Arctic Aß and wild-type Aß42. The selective increase of a single type of parenchymal Aß deposit suggests that different pathways lead to formation of diffuse and compact plaques. These findings could have general implications for Alzheimer's disease pathogenesis and particular relevance to patients heterozygous for the Arctic APP mutation. Moreover, it further illustrates how Aß neuropathologic features can be manipulated in vivo by mechanisms similar to those originally conceptualized in prion research.

Genetic deletion and pharmacological inhibition of Nogo-66 receptor impairs cognitive outcome after traumatic brain injury in mice.

Functional recovery is markedly restricted following traumatic brain injury (TBI), partly due to myelin-associated inhibitors including Nogo-A, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp), that all bind to the Nogo-66 receptor-1 (NgR1). In previous studies, pharmacological neutralization of both Nogo-A and MAG improved outcome following TBI in the rat, and neutralization of NgR1 improved outcome following spinal cord injury and stroke in rodent models. However, the behavioral and histological effects of NgR1 inhibition have not previously been evaluated in TBI. We hypothesized that NgR1 negatively influences behavioral recovery following TBI, and evaluated NgR1(-/-) mice (NgR1(-/-) study) and, in a separate study, soluble NgR1 infused intracerebroventricularly immediately post-injury to neutralize NgR1 (sNgR1 study) following TBI in mice using a controlled cortical impact (CCI) injury model. In both studies, motor function, TBI-induced loss of tissue, and hippocampal beta-amyloid immunohistochemistry were not altered up to 5 weeks post-injury. Surprisingly, cognitive function (as evaluated with the Morris water maze at 4 weeks post-injury) was significantly impaired both in NgR1(-/-) mice and in mice treated with soluble NgR1. In the sNgR1 study, we evaluated hippocampal mossy fiber sprouting using the Timm stain and found it to be increased at 5 weeks following TBI. Neutralization of NgR1 significantly increased mossy fiber sprouting in sham-injured animals, but not in brain-injured animals. Our data suggest a complex role for myelin-associated inhibitors in the behavioral recovery process following TBI, and urge caution when inhibiting NgR1 in the early post-injury period.

Animal models of amyloid-beta-related pathologies in Alzheimer's disease.

In the early 1990s, breakthrough discoveries on the genetics of Alzheimer's disease led to the identification of missense mutations in the amyloid-beta precursor protein gene. Research findings quickly followed, giving insights into molecular pathogenesis and possibilities for the development of new types of animal models. The complete toolbox of transgenic techniques, including pronuclear oocyte injection and homologous recombination, has been applied in the Alzheimer's disease field, to produce overexpressors, knockouts, knockins and regulatable transgenics. Transgenic models have dramatically advanced our understanding of pathogenic mechanisms and allowed therapeutic approaches to be tested. Following a brief introduction to Alzheimer's disease, various nontransgenic and transgenic animal models are described in terms of their values and limitations with respect to pathogenic, therapeutic and functional understandings of the human disease.

Genetic and pharmacological evidence of intraneuronal Abeta accumulation in APP transgenic mice.

Intraneuronal punctate immunostaining in Alzheimer's disease brain and amyloid-beta precursor protein (APP) transgenic mice has been suggested to represent Abeta, but this is somewhat controversial. Here we show that both biochemical Abeta levels and intraneuronal immunostaining are reduced in APP transgenic mice when gamma-secretase is inhibited. Moreover, BACE-1 deficient APP transgenic mice show neither Abeta production nor intraneuronal immunostaining. Our findings suggest that the punctate immunostaining with APP antibodies is due to Abeta that has accumulated inside neurons. Similar type of intraneuronal Abeta accumulation, which precedes senile plaque formation, may link Abeta to tauopathy and neurodegeneration in Alzheimer's disease pathogenesis.

A highly insoluble state of Abeta similar to that of Alzheimer's disease brain is found in Arctic APP transgenic mice.

Amyloid-beta (Abeta) is a major drug target in Alzheimer's disease. Here, we demonstrate that deposited Abeta is SDS insoluble in tgAPP-ArcSwe, a transgenic mouse model harboring the Arctic (E693G) and Swedish (KM670/671NL) APP mutations. Formic acid was needed to extract the majority of deposited Abeta in both tgAPP-ArcSwe and Alzheimer's disease brain, but not in a commonly used type of mouse model with the Swedish mutation alone. Interestingly, the insoluble state of Arctic Abeta was determined early on and did not gradually evolve with time. In tgAPP-ArcSwe, Abeta plaques displayed a patchy morphology with bundles of Abeta fibrils, whereas amyloid cores in tgAPP-Swe were circular with radiating fibrils. Amyloid was more densely stacked in tgAPP-ArcSwe, as demonstrated with a conformation sensitive probe. A reduced increase in plasma Abeta was observed following acute administration of an Abeta antibody in tgAPP-ArcSwe, results that might imply reduced brain to plasma Abeta efflux. TgAPP-ArcSwe, with its insoluble state of deposited Abeta, could serve as a complementary model to better predict the outcome of clinical trials.