Background-We evaluated the amounts of amyloid-beta (Aβ) peptides in the central nervous system (CNS) and in reservoirs outside the CNS and their potential impact on Aβ plasma levels and Alzheimer's disease (AD) pathology.

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 experiments 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.

Alzheimer's disease (AD) is characterized by the accumulation of extracellular insoluble amyloid, primarily derived from polymerized amyloid-␤ (A␤) peptides. We characterized the chemical composition of the A␤ peptides deposited in the brain parenchyma and cerebrovascular walls of triple transgenic Tg-SwDI mice that produce a rapid and profuse A␤ accumulation. The processing of the N-and C-terminal regions of mutant A␤PP differs substantially from humans because the brain parenchyma accumulates numerous, diffuse, nonfibrillar plaques, whereas the thalamic microvessels harbor overwhelming amounts of compact, fibrillar, thioflavine-S-and apolipoprotein E-positive amyloid deposits. The abundant accretion of vascular amyloid, despite low A␤PP transgene expression levels, suggests that inefficient A␤ proteolysis because of conformational changes and dimerization may be key pathogenic factors in this animal model. The disruption of amyloid plaque cores by immunotherapy is accompanied by increased perivascular deposition in both humans and transgenic mice. This analogous susceptibility and response to the disruption of amyloid deposits suggests that Tg-SwDI mice provide an excellent model in which to study the functional aftermath of immunotherapeutic interventions. These mice might also reveal new avenues to promote amyloidogenic A␤PP processing and fundamental insights into the faulty degradation and clearance of A␤ in AD, pivotal issues in understanding AD pathophysiology and the assessment of new therapeutic agents. Alzheimer's disease (AD) dementia is affecting an escalating proportion of the elderly population because of a dramatic increase in life expectancy. This neurodegenerative disorder is characterized by the profuse accumulation of extracellular insoluble amyloid in cerebral vessels and senile plaques, which are mainly composed of amyloid fibrils derived from polymerized amyloid-␤ (A␤) peptides. Amyloid-␤40/42 peptides are generated from the proteolytic degradation of the amyloid-␤ precursor protein (A␤PP) by the action of the ␤-and ␥-secretases. Amyloid-␤ peptides are very insoluble and resistant to subsequent proteolytic degradation because they contain a segment of the hydrophobic transmembrane domain of A␤PP. The prominent amyloid buildup associated with AD has resulted in the amyloid cascade hypothesis in which amyloid plays a fundamental mechanistic role in the pathogenesis and the emergence of dementia. A second relevant lesion in the AD brain is the accumulation of neurofibrillary tangles and neuropil threads that are mainly composed of hyperphosphorylated tau, a microtubule-associated protein.To determine the mechanisms leading to amyloid deposition and its clearance as well as its pathophysiological effects on brain tissue, several transgenic (Tg) mice have been engineered that carry familial AD A␤PP mutations with suitable promoters to accelerate the deposition of A␤

Amyloid-β (Aβ) peptides are intimately involved in the inflammatory pathology of atherosclerotic vascular disease (AVD) and Alzheimer's disease (AD). Although substantial amounts of these peptides are produced in the periphery, their role and significance to vascular disease outside the brain requires further investigation. Amyloid-β peptides present in the walls of human aorta atherosclerotic lesions as well as activated and non-activated human platelets were isolated using sequential size-exclusion columns and HPLC reverse-phase methods. The Aβ peptide isolates were quantified by ELISA and structurally analyzed using MALDI-TOF mass spectrometry procedures. Our experiments revealed that both aorta and platelets contained Aβ peptides, predominately Aβ40. The source of the Aβ pool in aortic atherosclerosis lesions is probably the activated platelets and/or vascular wall cells expressing APP/PN2. Significant levels of Aβ42 are present in the plasma, suggesting that this reservoir makes a minor contribution to atherosclerotic plaques. Our data reveal that although aortic atherosclerosis and AD cerebrovascular amyloidosis exhibit clearly divergent end-stage manifestations, both vascular diseases share some key pathophysiological promoting elements and pathways. Whether they happen to be deposited in vessels of the central nervous system or atherosclerotic plaques in the periphery, Aβ peptides may promote and perhaps synergize chronic inflammatory processes which culminate in the degeneration, malfunction and ultimate destruction of arterial walls.

We investigated the morphology and biochemistry of the amyloid-beta (Abeta) peptides produced in TgCRND8 Tg mice carrying combined amyloid precursor protein (APP) Swedish (K670M/N671L) and Indiana (V717F) mutations. Histological analyses employing amyloid-specific staining and electron microscopy revealed that the TgCRND8 Tg mice produce an aggressive pathology, evident as early as 3 months of age, that is a composite of core plaques and peculiar floccular diffuse parenchymal deposits. The Abeta peptides were purified using combined FPLC-HPLC, Western blots, and immunoprecipitation methods and characterized by MALDI-TOF/SELDI-TOF mass spectrometry. The C-terminal APP peptides, assessed by Western blot experiments and mass spectrometry, suggested an alteration in the order of secretase processing, yielding a C-terminal fragment pattern that is substantially different from that observed in sporadic Alzheimer's disease (AD). This modified processing pattern generated longer Abeta peptides, as well as those ending at residues 40/42/43, which may partially explain the early onset and destructive nature of familial AD caused by APP mutations. Despite an aggressive pathology that extended to the cerebellum and white matter, these animals tolerated the presence of an imposing amount of Abeta load. Abeta immunization resulted in an impressive 7-fold reduction in the number of amyloid core plaques and, as previously demonstrated, a significant memory recovery. However, given the phylogenetic distance and the differences in APP processing and Abeta chemistry between Tg mice and AD, caution should be applied in projecting mouse therapeutic interventions onto human subjects.