Brain Parenchymal and Microvascular Amyloid in Alzheimer's Disease

Brains of patients with Alzheimer disease/senile dementia of Alzheimer type (AD/SDAT) develop a progressive accumulation of amyloid, which deposits primarily in the form of characteristic parenchyma!'plaques' (senile or neuritic plaques/SP's) and as mural deposits in the walls of capillaries and arterioles (cerebral amyloid angiopa-thy/CAA). A major component of this amyloid is a small and unique peptide composed of 39–43 amino acids, beta/A4, which is cleaved from a much larger precursor protein (APP) that has several isoforms. Brain amyloid can be detected in autopsy or biopsy brain tissue by classical, immunohistochemical and ultrastructural (including immuno-electron microscopic) methods of varying sensitivity and specificity. Beta/A4 amyloid deposition is remarkably variable (e.g. predominantly parenchyma! or vascular, or a mixture of parenchymal and vascular) among patients with AD/SDAT. Despite its abundance in the brains of AD/SDAT patients, the precise role of beta/A4 in the pathogenesis of the neurological deficit, neocortical atrophy and progressive synapse loss associated with AD/SDAT has yet to be determined. However, mutations in the gene that encodes APP are clearly associated with familial AD syndromes in which there is significant brain amyloid deposition. CAA, in addition to its association with AD/SDAT, can result in hemorrhagic and (possibly) ischemic forms of stroke. Work with recently developed transgenic mice which express large amounts of beta/A4 in the central nervous system is likely to elucidate mechanisms by which the protein is selectively deposited in the brain in a parenchymal or microvascular form, and how it contributes to the pathogenesis of neurodegeneration.     

The AMY Antigen Co-Occurs with Aβ and Follows Its Deposition in the Amyloid Plaques of Alzheimer’s Disease and Down Syndrome

Novel plaque-like "AMY" lesions were recently described in the brains of patients with Alzheimer's disease (AD). Using three Abeta antibodies, we now document the co-occurrence of AMY immunoreactivity (IR) with amyloid beta-peptide (Abeta) in the large majority of plaques in AD brain. AMY IR was detected in many compacted plaques, whereas its co-localization with early, diffuse Abeta deposits was rare. AMY IR overlapped considerably or fully with Abeta and, in more severely affected AD brains, decorated the periphery of some plaques. In a temporal series of 29 Down syndrome (DS) brains from patients aged 12 to 73 years, the earliest AMY IR was detected in some plaques at age 15, following the earliest appearance of Abeta plaques (age 12 years), and then accrued within a subset of Abeta deposits, namely, the more spherical, compacted plaques. Brains from DS patients 29 years and older showed AMY staining in many Abeta plaques, as seen in AD. Brains from eight monkeys aged 17 to 34 years and thirty APP transgenic mice aged 8 to 20 months showed Abeta IR but no AMY IR. We conclude that AMY IR represents an amyloid-associated antigen that co-deposits in most but not all Abeta plaques in AD and DS and that accumulation of the AMY antigen follows Abeta deposition in plaques.     

Image analysis microspectroscopy shows that neurons participate in the genesis of a subset of early primitive (diffuse) senile plaques.

Amyloid is a component of the senile plaques that characterize one of the major neuropathologic changes in patients with Alzheimer's disease (AD). The sequence of events leading to the accumulation of amyloid precursors in senile plaques is unknown. In previous studies, the authors have shown that congophilic deposits in a subset of mature amyloid plaques are angiocentric. In this study, the authors used image analysis microspectroscopy and an antibody directed against a synthetic beta-protein (beta) or A4 sequence to examine the distribution patterns of this protein in serial sections from brains of patients with AD and in normal aged brains after quantitative immunohistochemistry. Image analysis of early primitive plaques disclosed two main patterns of early beta/A4 deposition, which consisted of neurocentric and angiocentric decreasing concentration gradients. In most instances, these gradients were not recognizable by the naked eye but appeared strikingly conspicuous after image subtraction and pseudocoloring. The described neurocentric gradients suggest that deposition of this protein, in at least some early primitive plaques, is related to neurons and possibly originates from these cells. The opposite viewpoint, i.e., that peripherally synthesized beta/A4 protein would 'sink in' toward neurons, is not supported because in very early plaques the highest immunoreactivity within the gradient was the neuronal body itself. A hypothesis is offered to reconcile the presence of both neurocentric and angiocentric depositions of these substances.     

Amyloid imaging using fluorine-19 magnetic resonance imaging (19F-MRI)

The formation of senile plaques followed by the deposition of amyloid-β is the earliest pathological change in Alzheimer’s disease. Thus, the detection of senile plaques remains the most important early diagnostic indicator of Alzheimer’s disease. Amyloid imaging is a noninvasive technique for visualizing senile plaques in the brains of Alzheimer’s patients using positron emission tomography (PET) or magnetic resonance imaging (MRI). Because fluorine-19 (¹⁹F) displays an intense nuclear magnetic resonance signal and is almost non-existent in the body, targets are detected with a higher signal-to-noise ratio using appropriate fluorinated contrast agents. The recent introduction of high-field MRI allows us to detect amyloid depositions in the brain of living mouse using ¹⁹F-MRI. So far, at least three probes have been reported to detect amyloid deposition in the brain of transgenic mouse models of Alzheimer’s disease; (E,E)-1-fluoro-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (FSB), 1,7-bis(4′-hydroxy-3′-trifluoromethoxyphenyl)-4-methoxycarbonylethyl-1,6-heptadiene3,5-dione (FMeC1, Shiga-Y5) and 6-(3′,6′,9′,15′,18′,21′-heptaoxa-23′,23′,23′-trifluorotricosanyloxy)-2-(4′-dimethylaminostyryl)benzoxazole (XP7, Shiga-X22). This review presents the recent advances in amyloid imaging using ¹⁹F-MRI, including our own studies.     

Catecholaminergic neuronal loss in locus coeruleus of aged female dtg APP/PS1 mice

Alzheimer's disease (AD) is the most common type of dementia afflicting the elderly. In addition to the presence of cortical senile plaques and neurofibrillary tangles, AD is characterized at autopsy by extensive degeneration of brainstem locus coeruleus (LC) neurons that provide noradrenergic innervation to cortical neuropil, together with relative stability of dopaminergic neuron number in substantia nigra (SN) and ventral tegmental area (VTA). The present study used design-based stereological methods to assess catecholaminergic neuronal loss in brains of double transgenic female mice that co-express two human mutations associated with familial AD, amyloid precursor protein (APP_swe) and presenilin-1 (PS1_ΔE9). Mice were analyzed at two age groups, 3–6 months and 16–23 months, when deposition of AD-type β-amyloid (Aβ) plaques occurs in cortical brain regions. Blocks of brain tissue containing the noradrenergic LC nucleus and two nuclei of dopaminergic neurons, the SN and VTA, were sectioned and sampled in a systematic-random manner and immunostained for tyrosine hydroxylase (TH), a specific marker for catecholaminergic neurons. Using the optical fractionator method we found a 24% reduction in the total number of TH-positive neurons in LC with no changes in SN-VTA of aged dtg APP/PS1 mice compared with non-transgenic controls. No significant differences were observed in numbers of TH-positive neurons in LC or SN-VTA in brains of young female dtg APP/PS1 mice compared to their age-matched controls. The findings of selective neurodegeneration of LC neurons in the brains of aged female dtg APP/PS1 mice mimic the neuropathology in the brains of AD patients at autopsy. These findings support the use of murine models of Aβ deposition to develop novel strategies for the therapeutic management of patients afflicted with AD.     

Chlamydia pneumoniae induces Alzheimer-like amyloid plaques in brains of BALB/c mice

Amyloid deposits resembling plaques found in Alzheimer's disease (AD) brains were formed in the brains of non-transgenic BALB/c mice following intranasal infection with Chlamydia pneumoniae. The mice were infected at 3 months of age with C. pneumoniae isolated from an AD brain. Infection was confirmed by light and electron microscopy in olfactory tissues of the mice. C. pneumoniae was still evident in these tissues 3 months after the initial infection indicating that a persistent infection had been established. Amyloid beta (Abeta) 1-42 immunoreactive deposits were identified in the brains of infected BALB/c mice up to 3 months post-infection with the density, size, and number of deposits increasing as the infection progressed. A subset of deposits exhibited thioflavin-s labeling. Intracellular Abeta1-42 labeling was observed in neuronal cells. Experimental induction of amyloid deposition in brains of non-transgenic BALB/c mice following infection with C. pneumoniae may be a useful model for furthering our understanding of mechanisms, linked to infection, involved in the initiation of the pathogenesis of sporadic AD.     

Mostly separate distributions of CLAC- versus Abeta40- or thioflavin S-reactivities in senile plaques reveal two distinct subpopulations of beta-amyloid deposits

Collagenous Alzheimer amyloid plaque component (CLAC) is a unique non-Abeta amyloid component of senile plaques (SP) derived from a transmembrane collagen termed CLAC-precursor. Here we characterize the chronological and spatial relationship of CLAC with other features of SP amyloid in the brains of patients with Alzheimer's disease (AD), Down syndrome (DS), and of PSAPP transgenic mice. In AD and DS cerebral cortex, CLAC invariably colocalized with Abeta42 but often lacked Abeta40- or thioflavin S (thioS)-reactivities. Immunoelectron microscopy of CLAC-positive SP showed labeling of fibrils that are more loosely dispersed compared to typical amyloid fibrils in CLAC-negative SP. In DS cerebral cortex, diffuse plaques in young patients were negative for CLAC, whereas a subset of SP became CLAC-positive in patients aged 35 to 50 years, before the appearance of Abeta40. In DS cases over 50 years of age, Abeta40-positive SP dramatically increased, whereas CLAC burden remained at a constant level. In PSAPP transgenic mice, CLAC was positive in the diffuse Abeta deposits surrounding huge-cored plaques. Thus, CLAC and Abeta40 or thioS exhibit mostly separate distribution patterns in SP, suggesting that CLAC is a relatively early component of SP in human brains that may have inhibitory effects against the maturation of SP into beta-sheet-rich amyloid deposits.     

Detection of Aβ Plaques by a Novel Specific MRI Probe Precursor CR‐BSA‐(Gd‐DTPA)n in APP/PS1 Transgenic Mice

Amyloid plaques are one of the hallmarks of Alzheimer's disease (AD). The lack of specific probes that can detect individual senile plaques in AD has prompted the development of magnetic resonance imaging (MRI) probes. In this study, based on DTPA‐gadolinium (III) and congo red (CR), a novel specific MRI probe precursor CR‐BSA‐(Gd‐DTPA)n was successfully synthesized. Its ability to bind to amyloid plaques was evaluated by brain sections from APP/PS1 transgenic mice. Its specificity for Aβ plaques was further demonstrated by immunohistochemistry (IHC) staining with the monoclonal antibody to the Aβ protein. Meanwhile, the amyloid deposits detected by the CR‐BSA‐(Gd‐DTPA)n were matched to the amyloid deposits detected by Aβ specific antibody. We also found that a few amyloid‐like deposits which was not detected by IHC. The findings indicated that the probe perhaps could detect the neurofibrillary tangles (NFT) similar to the effect of CR itself, and this will be verified in future experiments. The works suggested that the Aβ protein‐specific magnetic resonance contrast agent precursor CR‐BSA‐(Gd‐DTPA)n can be used as a potential fluorescence and MR multi‐modal imaging probe precursor to display individual senile plaques in AD. Anat Rec, 2010. © 2010 Wiley‐Liss, Inc.     

PET imaging with [18F]AV-45 in an APP/PS1-21 murine model of amyloid plaque deposition

Alzheimer's disease (AD), the most common age-related neurodegenerative disorder, is characterized by the accumulation of β-amyloid peptide. In man, [18F]AV-45 with positron emission tomography (PET) is currently studied and used to track in vivo amyloid accumulation. Here, [18F]-AV45-PET was used to visualize amyloid deposition in a transgenic murine model of amyloidosis (APP/PS1-21). Studies were performed ex vivo by autoradiography and in vivo by microPET. Autoradiograms of the brain sections highlighted an increased uptake of [18F]AV-45 in APP/PS1-21 mice compared with age-matched control mice. From 8 months, an intense labeling was observed in cortex, hippocampus, and striatum. The marked accumulation of radiotracer was found in close association with thioflavin S-positive amyloid plaques. The longitudinal microPET assessment, performed from 3 to 12 months of age, demonstrated an increased [18F]AV-45 uptake in APP/PS1-21 compared with control mice. The elevated tracer uptake was increased in association with age. This study opens the possibility of [18F]AV-45, coupled with microPET, to visualize and quantitatively measure amyloid deposits in the brains of living APP/PS1 mice.     

Alpha 1-antichymotrypsin is present in diffuse senile plaques. A comparative study of beta-protein and alpha 1-antichymotrypsin immunostaining in the Alzheimer brain.

Immunocytochemical examinations of the brains of patients with senile dementia of the Alzheimer type, Down''s syndrome, and Gerstmann-Sträusslar-Scheinker disease were performed to clarify the relationship between alpha 1-antichymotrypsin and senile plaque amyloids. Alpha 1-antichymotrypsinlike immunoreactivity was enhanced by protease digestion but not by formic acid pretreatment. Almost all of the diffuse plaques and some small amyloid deposits, which were widely distributed in the cerebral cortex and/or subcortical regions of SDAT brains, were labeled by alpha 1-antichymotrypsin immunostaining. All types of senile plaques, eosinophilic tangles, and some neurons and astrocytes were labeled by alpha 1-antichymotrypsin staining. Diffuse plaques in a Down''s syndrome frontal lobe and in a senile dementia of the Alzheimer type cerebellum also were labeled by alpha 1-antichymotrypsin immunostaining. However neither subpial amyloid deposits nor subcortical small amyloid deposits could be detected by alpha 1-antichymotrypsin immunostaining. Kuru plaques in a Gerstmann-Sträusslar-Scheinker disease cerebellum also were not labeled by alpha 1-antichymotrypsin immunostaining. These results suggest that alpha 1-antichymotrypsin is associated with the early to late stages of amyloid deposition and senile plaque formation in senile demential of the Alzheimer type.     

Dense-core senile plaques in the Flemish variant of Alzheimer's disease are vasocentric

Alzheimer's disease (AD) is characterized by deposition of beta-amyloid (Abeta) in diffuse and senile plaques, and variably in vessels. Mutations in the Abeta-encoding region of the amyloid precursor protein (APP) gene are frequently associated with very severe forms of vascular Abeta deposition, sometimes also accompanied by AD pathology. We earlier described a Flemish APP (A692G) mutation causing a form of early-onset AD with a prominent cerebral amyloid angiopathy and unusually large senile plaque cores. The pathogenic basis of Flemish AD is unknown. By image and mass spectrometric Abeta analyses, we demonstrated that in contrast to other familial AD cases with predominant brain Abeta42, Flemish AD patients predominantly deposit Abeta40. On serial histological section analysis we further showed that the neuritic senile plaques in APP692 brains were centered on vessels. Of a total of 2400 senile plaque cores studied from various brain regions from three patients, 68% enclosed a vessel, whereas the remainder were associated with vascular walls. These observations were confirmed by electron microscopy coupled with examination of serial semi-thin plastic sections, as well as three-dimensional observations by confocal microscopy. Diffuse plaques did not associate with vessels, or with neuritic or inflammatory pathology. Together with earlier in vitro data on APP692, our analyses suggest that the altered biological properties of the Flemish APP and Abeta facilitate progressive Abeta deposition in vascular walls that in addition to causing strokes, initiates formation of dense-core senile plaques in the Flemish variant of AD.     

Amyloid cored plaques in Tg2576 transgenic mice are characterized by giant plaques,slightly activated microglia,and the lack of paired helical filament-typed,dystrophic neurites

We examined the brains of Tg2576 transgenic mice carrying human amyloid precursor protein with the Swedish mutation and Alzheimer's disease (AD) by means of immunohistochemistry and electron microscopy to clarify the characteristics of amyloid-associated pathology in the transgenic mice. In 12- to 29-month-old Tg2576 mice, congophilic cored plaques in the neocortex and hippocampus were labeled by all of the Abeta1-, Abeta40- and 42-specific antibodies, as seen in the classical plaques in AD. However, large-sized (>50 micro m in core diameter) plaques were seen more frequently in the older mice (18-29 months) than in those with AD (approximately 20% vs 2% in total cored plaques), and Tg2576 mice contained giant plaques (>75 micro m in core diameter), which were almost never seen in the brain of those with AD. Neither thread-like structures nor peripheral coronas were observed in the cored plaques of the transgenic mice in the silver impregnations. Immunohistochemically, plaque-accompanied microglia showed a slight enlargement of the cytoplasm with consistent labeling of Mac-1 and macrosialin (murine CD68), and with partial labeling of Ia antigen and macrophage-colony stimulating factor receptor. Ultrastructurally, the microglia surrounding the extracellular amyloid fibrils in the large, cored plaques showed some organella with phagocytic activity, such as secondary lysosomal, dense bodies, but intracellular amyloid fibrils were not evident. Dystrophic neurites in the plaques of the transgenic mice contained many dense multilaminar bodies, but no paired helical filaments. Our results suggest that giant cored plaques without coronas or paired helical filament-typed, dystrophic neurites are characteristic in Tg2576 mice, and that plaque-associated microglia in transgenic mice are activated to be in phagocytic function but not sufficient enough to digest extracellularly deposited amyloid fibrils.     

Type-specific evolution of amyloid plaque and angiopathy in APPsw mice

To clarify how Aβ deposits start in the brain, we examined the early to late stages of senile plaques and amyloid angiopathy in APPsw mice. All types of human senile plaques were observed in the mouse brains. The premature forms of cored plaques appeared first in the cerebral cortex of mice at 7–8 months old. Then, amyloid angiopathy emerged, followed by diffuse plaques consisting of Aβ1–42. Modifications of the N-terminus of Aβ were late phase phenomena. The premature forms of cored plaques were composed of central Aβ1–40 amyloid cores, surrounding amorphous Aβ1–42 deposits, and accumulation of Aβ1–42 in some peripheral cells. These cells were incorporated in amyloid cores, and these plaques developed to large cored plaques composed of Aβ1–40 and Aβ1–42. The size and number of cored plaques were increased with age. These findings indicate different evolution paths for cored plaques and diffuse plaques, and suggest the presence of a pathway that initiates with the intracellular accumulation of Aβ1–42 and leads to the development of classic plaques in human brain tissues.     

Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the london mutant of human APP in neurons

Deposition of amyloid beta-peptide (Abeta) in cerebral vessel walls (cerebral amyloid angiopathy, CAA) is very frequent in Alzheimer's disease and occurs also as a sporadic disorder. Here, we describe significant CAA in addition to amyloid plaques, in aging APP/Ld transgenic mice overexpressing the London mutant of human amyloid precursor protein (APP) exclusively in neurons. The number of amyloid-bearing vessels increased with age, from approximately 10 to >50 per coronal brain section in APP/Ld transgenic mice, aged 13 to 24 months. Vascular amyloid was preferentially deposited in arterioles and ranged from small focal to large circumferential depositions. Ultrastructural analysis allowed us to identify specific features contributing to weakening of the vessel wall and aneurysm formation, ie, disruption of the external elastic lamina, thinning of the internal elastic lamina, interruption of the smooth muscle layer, and loss of smooth muscle cells. Biochemically, the much lower Abeta42:Abeta40 ratio evident in vascular relative to plaque amyloid, demonstrated that in blood vessel walls Abeta40 was the more abundant amyloid peptide. The exclusive neuronal origin of transgenic APP, the high levels of Abeta in cerebrospinal fluid compared to plasma, and the specific neuroanatomical localization of vascular amyloid strongly suggest specific drainage pathways, rather than local production or blood uptake of Abeta as the primary mechanism underlying CAA. The demonstration in APP/Ld mice of rare vascular amyloid deposits that immunostained only for Abeta42, suggests that, similar to senile plaque formation, Abeta42 may be the first amyloid to be deposited in the vessel walls and that it entraps the more soluble Abeta40. Its ability to diffuse for larger distances along perivascular drainage pathways would also explain the abundance of Abeta40 in vascular amyloid. Consistent with this hypothesis, incorporation of mutant presenilin-1 in APP/Ld mice, which resulted in selectively higher levels of Abeta42, caused an increase in CAA and senile plaques. This mouse model will be useful in further elucidating the pathogenesis of CAA and Alzheimer's disease, and will allow testing of diagnostic and therapeutic strategies.     

Association of Microglia with Amyloid Plaques in Brains of APP23 Transgenic Mice

Microglia are a key component of the inflammatory response in the brain and are associated with senile plaques in Alzheimer's disease (AD). Although there is evidence that microglial activation is important for the pathogenesis of AD, the role of microglia in cerebral amyloidosis remains obscure. The present study was undertaken to investigate the relationship between beta-amyloid deposition and microglia activation in APP23 transgenic mice which express human mutated amyloid-beta precursor protein (betaPP) under the control of a neuron-specific promoter element. Light microscopic analysis revealed that the majority of the amyloid plaques in neocortex and hippocampus of 14- to 18- month-old APP23 mice are congophilic and associated with clusters of hypertrophic microglia with intensely stained Mac-1- and phosphotyrosine-positive processes. No association of such activated microglia was observed with diffuse plaques. In young APP23 mice, early amyloid deposits were already of dense core nature and were associated with a strong microglial response. Ultrastructurally, bundles of amyloid fibrils, sometimes surrounded by an incomplete membrane, were observed within the microglial cytoplasm. However, microglia with the typical characteristics of phagocytosis were associated more frequently with dystrophic neurites than with amyloid fibrils. Although the present observations cannot unequivocally determine whether microglia are causal, contributory, or consequential to cerebral amyloidosis, our results suggest that microglia are involved in cerebral amyloidosis either by participating in the processing of neuron-derived betaPP into amyloid fibrils and/or by ingesting amyloid fibrils via an uncommon phagocytotic mechanism. In any case, our observations demonstrate that neuron-derived betaPP is sufficient to induce not only amyloid plaque formation but also amyloid-associated microglial activation similar to that reported in AD. Moreover, our results are consistent with the idea that microglia activation may be important for the amyloid-associated neuron loss previously reported in these mice.     

Progress toward valid transgenic mouse models for Alzheimer's disease.

A transgenic mouse model for Alzheimer's disease (AD) should mimic the age-dependent accumulation of beta-amyloid plaques, neurofibrillary tangles, neuronal cell death as well as display memory loss and behavioral deficits. Age-dependent accumulation of A beta deposits in mouse brain has been achieved in mice overexpressing mutant alleles of the amyloid precursor protein (APP). In contrast, mice bearing mutant alleles of the presenilin genes show increased production of the A beta42 peptide, but do not form amyloid deposits unless mutant alleles of APP are also overproduced. Furthermore, the onset of A beta deposition is greatly accelerated, paralleling the involvement of presenilins in early onset AD. Studies of APP and presenilin transgenic mice have shown 1) the absence of a requirement for a maturation step in dense core plaque formation, 2) evidence that beta-amyloid deposition is directed by regional factors, and 3) behavioral deficits are observed before A beta deposition. Crosses of APP transgenic mice with mice modified for known AD risk factors and "humanizing" the mouse may be necessary for complete replication of AD.     

Alzheimer's amyloid precursor protein-positive degenerative neurites exist even within kuru plaques not specific to Alzheimer's disease.

To clarify the relationship between amyloid formation and amyloid precursor protein (APP), the brain sections from eight patients with Alzheimer''s disease (AD) and four with Gerstmann-Sträussler Syndrome (GSS) were investigated immunohistochemically by the double-immunostaining method. In AD, most APP-positive senile plaques belong to classical plaques or primitive plaques, whereas in diffuse plaques, APP-positive neuritic components are rarely observed. The authors documented that anti-APP-labeled degenerative neurites surrounding kuru plaques in all four GSS patients. These kuru plaques were verified by double immunostaining using anti-prion protein and anti-APP. The APP-positive structures in kuru plaques were almost identical with those seen in the classical plaques in AD. The authors concluded that APP-positive degenerative neurites are not an early event in the amyloid formation of senile plaques. It is therefore postulated that depositions of beta/A4 and prion proteins are primary events that may involve the surrounding microenvironment and result in the secondary formation of APP-positive degenerative neurites, not specific to AD.     

The lipophilic metal chelator DP-109 reduces amyloid pathology in brains of human beta-amyloid precursor protein transgenic mice

Metals such as zinc, copper and iron contribute to aggregation of amyloid-β (Aβ) protein and deposition of amyloid plaques in Alzheimer’s disease (AD). We examined whether the lipophilic metal chelator DP-109 inhibited these events in aged female hAβPP-transgenic Tg2576 mice. Daily gavage administration of DP-109 for 3 months markedly reduced the burden of amyloid plaques and the degree of cerebral amyloid angiopathy in brains, compared to animals receiving vehicle treatment. Moreover, DP-109 treatment appeared to facilitate the transition of Aβ from insoluble to soluble forms in the cerebrum. These results further support the hypothesis that endogenous metals are involved in the deposition of aggregated Aβ in brains of AD patients, and that metal chelators may be useful therapeutic agents in the treatment of AD.     

The 2,6-disubstituted naphthalene derivative FDDNP labeling reliably predicts Congo red birefringence of protein deposits in brain sections of selected human neurodegenerative diseases

Deposition of conformationally altered proteins prominently characterizes pathogenesis and pathomorphology of a number of neurodegenerative disorders. 2-(1-{6-[(2-[F-18]fluoroethyl) (methyl)amino]-2-naphthyl} ethylidene) malononitrile ([F-18]FDDNP), a hydrophobic, viscosity-sensitive, solvent-sensitive, fluorescent imaging probe has been used with positron emission tomography to visualize brain pathology in the living brain of Alzheimer disease (AD) patients. Its non-radiofluorinated analog FDDNP was shown to label senile plaques and neurofibrillary tangles (NFTs) in brain tissue sections. This work aimed at evaluating FDDNP labeling of various protein deposits in fixed, paraffin-embedded brain tissue sections of selected neurodegenerative disorders: AD, cerebral amyloid angiopathy (CAA), transmissible spongiform encephalopathies, progressive supranuclear palsy (PSP), Pick disease (PiD), Parkinson disease, dementia with Lewy bodies, multiple system atrophy (MSA). Cerebral hypertensive vascular hyalinosis (HVH) was used as negative control. Significant agreement between amyloid histochemical properties and FDDNP labeling of the deposits was established. FDDNP labeling showed high positive predictive value for birefringence in senile plaques and NFTs in AD, prion plaques and amyloid deposits in CAA. No FDDNP labeled structures were observed in HVH, PSP, PiD or MSA tissue sections. Our findings may be of significant value for the detection of neuropathological aggregates with [F-18]FDDNP in some of these disorders in the living brain of human subjects.     

"Emerging Alzheimer's disease therapies: focusing on the future"

The Center for Neurodegenerative Disease Research (CNDR) organized a 1 day symposium entitled "Emerging Alzheimer's disease Therapies: Focusing On The Future" on November 7th, 2001 at the University of Pennsylvania in Philadelphia, PA. The agenda (Fig. 1) focused on novel therapies for Alzheimer's disease (AD) designed to prevent/eliminate Abeta deposits in the brains of AD patients. While fibrillar Abeta deposits known as senile plaques (SPs) and intraneuronal tau fibrils known as neurofibrillary tangles (NFTs) are diagnostic of AD, >50% of patients with familial or sporadic AD as well as elderly Down's syndrome patients with AD harbor a third type of brain amyloid known as Lewy bodies formed by intraneuronal alpha-synuclein fibrils. Thus, AD is a "triple brain amyloidosis" since three different proteins (tau, alpha-synuclein) or peptide fragments (Abeta) of a larger Abeta precursor protein (APP) fibrillize and aggregate into pathological deposits of amyloid within (NFTs, LBs) and outside (SPs) neurons in AD brains. The symposium is summarized here followed by reviews from symposium speakers who describe potential anti-Abeta therapies some of which are in clinical trials.