Mouse models of neurodegenerative disease: preclinical imaging and neurovascular component.

Neurodegenerative diseases represent great challenges for basic science and clinical medicine because of their prevalence, pathologies, lack of mechanism-based treatments, and impacts on individuals. Translational research might contribute to the study of neurodegenerative diseases. The mouse has become a key model for studying disease mechanisms that might recapitulate in part some aspects of the corresponding human diseases. Neurode- generative disorders are very complicated and multifacto- rial. This has to be taken in account when testing drugs. Most of the drugs screening in mice are very di cult to be interpretated and often useless. Mouse models could be condiderated a ‘pathway models’, rather than as models for the whole complicated construct that makes a human disease. Non-invasive in vivo imaging in mice has gained increasing interest in preclinical research in the last years thanks to the availability of high-resolution single-photon emission computed tomography (SPECT), positron emission tomography (PET), high eld Magnetic resonance, Optical Imaging scanners and of highly speci c contrast agents. Behavioral test are useful tool to characterize di erent ani- mal models of neurodegenerative pathology. Furthermore, many authors have observed vascular pathological features associated to the di erent neurodegenerative disorders. Aim of this review is to focus on the di erent existing animal models of neurodegenerative disorders, describe behavioral tests and preclinical imaging techniques used for diagnose and describe the vascular pathological features associated to these diseases

Potent amyloidogenicity and pathogenicity of Aβ43.

The amyloid-β peptide Aβ42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimer\u27s disease. However, the role of Aβ43, which is found just as frequently in the brains of affected individuals, remains unresolved. We generated knock-in mice containing a pathogenic presenilin-1 R278I mutation that causes overproduction of Aβ43. Homozygosity was embryonic lethal, indicating that the mutation involves a loss of function. Crossing amyloid precursor protein transgenic mice with heterozygous mutant mice resulted in elevated Aβ43, impairment of short-term memory and acceleration of amyloid-β pathology, which accompanied pronounced accumulation of Aβ43 in plaque cores similar in biochemical composition to those observed in the brains of affected individuals. Consistently, Aβ43 showed a higher propensity to aggregate and was more neurotoxic than Aβ42. Other pathogenic presenilin mutations also caused overproduction of Aβ43 in a manner correlating with Aβ42 and with the age of disease onset. These findings indicate that Aβ43, an overlooked species, is potently amyloidogenic, neurotoxic and abundant in vivo

Presenilin-1 280Glu→Ala Mutation Alters C-Terminal APP Processing Yielding Longer Aβ Peptides: Implications for Alzheimer’s Disease

Presenilin (PS) mutations enhance the production of the Aβ42 peptide that is derived from the amyloid precursor protein (APP). The pathway(s) by which the Aβ42 species is preferentially produced has not been elucidated, nor is the mechanism by which PS mutations produce early-onset dementia established. Using a combination of histological, immunohistochemical, biochemical, and mass spectrometric methods, we examined the structural and morphological nature of the amyloid species produced in a patient expressing the PS1 280Glu→Ala familial Alzheimer’s disease mutation. Abundant diffuse plaques were observed that exhibited a staining pattern and morphology distinct from previously described PS cases, as well as discreet amyloid plaques within the white matter. In addition to finding increased amounts of CT99 and Aβ42 peptides, our investigation revealed the presence of a complex array of Aβ peptides substantially longer than 42/43 amino acid residue species. The increased hydrophobic nature of longer Aβspecies retained within the membrane walls could impact the structure and function of plasma membrane and organelles. These C-terminally longer peptides may, through steric effects, dampen the rate of turnover by critical amyloid degrading enzymes such as neprilysin and insulin degrading enzyme. A complete understanding of the deleterious side effects of membrane bound Aβ as a consequence of γ-secretase alterations is needed to understand Alzheimer’s disease pathophysiology and will aid in the design of therapeutic interventions

Bapineuzumab Alters Aβ Composition: Implications for the Amyloid Cascade Hypothesis and Anti-Amyloid Immunotherapy

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 Aβ(42) levels as well as an increase in Aβ(40) which led to a corresponding significant decrease in Aβ(42):Aβ(40) 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