Sci. Aging Knowl. Environ., 8 March 2006
Vol. 2006, Issue 6, p. re1
[DOI: 10.1126/sageke.2006.6.re1]

The Development of Amyloid beta Protein Deposits in the Aged Brain

Dietmar R. Thal, Estibaliz Capetillo-Zarate, Kelly Del Tredici, and Heiko Braak

The authors are at the Department of Neuropathology, University of Bonn, D-53105 Bonn, Germany (D.R.T. and E.C.-Z.) and at the Institute for Clinical Neuroanatomy, J. W. Goethe University, D-60590 Frankfurt am Main, Germany (K.D.T. and H.B.). E-mail: Dietmar.Thal{at} (D.R.T.)

Key Words: senile plaques • amyloid beta protein • Alzheimer's disease • tau

Abstract: The deposition of amyloid beta protein (Abeta) in the human brain and the generation of neurofibrillary tangles are the histopathological hallmarks of Alzheimer's disease. Accumulation of Abeta takes place in senile plaques and in cerebrovascular deposits as a result of an imbalance between Abeta production and clearance. This Review describes the different types of Abeta deposits, which can be distinguished by their morphology and by the hierarchical involvement of distinct areas of the brain in Abeta deposition. The role of intracellular Abeta in Abeta deposition and the mechanism of Abeta toxicity are also discussed.


The deposition of the amyloid beta protein (Abeta ) in the human brain and the generation of neurofibrillary tangles (NFTs) are the histopathological hallmarks of Alzheimer's disease (AD, see also "Detangling Alzheimer's Disease") (1, 2). All types of cerebral, nonvascular Abeta deposits are typically referred to as "senile plaques" regardless of their morphology (3). Abeta deposits can also be seen in a large number of cognitively normal individuals (4-6). The major difference between these Abeta deposits and those found in AD patients is their distribution [see Thal Perspective and (5, 7, 8)]. In cognitively normal individuals, parenchymal and vascular Abeta deposits are usually restricted to the cerebral cortex, the basal ganglia (involved in movement control), the thalamus (sensory information, movement control, and limbic processing), and the hypothalamus (autonomic and limbic function). On the other hand, in AD patients, Abeta deposits are found in the midbrain, brain stem, and cerebellum, in addition to the brain regions potentially affected in cognitively normal individuals (8, 9). Similarly, NFT pathology extends into primary and secondary neocortical areas only in AD patients (5, 10). The expansion of Abeta deposition and NFT pathology is associated with synaptic and neuronal loss (11-17). Depending on their location in the brain and the point in time at which they appear, Abeta deposits can be distinguished by their morphology and protein content. This Review focuses on the characterization and distribution of senile plaques in different stages of AD pathogenesis and discusses the processes involved in their generation.

Classification of Senile Plaques

Senile plaques consist of fibrillary amyloid material, which can be seen both in electron microscopy and light microscopy (for example, in Campbell-Switzer silver-stained sections) and show a characteristic red-green birefringence in Congo red-stained sections (3, 18-20). They also stain with thioflavin S (3, 21). The amyloid fibrils are composed of aggregated Abeta peptides and display a beta-pleated sheet conformation (2, 22). Before forming fibrils, Abeta peptides aggregate into oligomers and produce Abeta-derived diffusible ligands (ADDLs) (23, 24). Mutations in the amino acid sequence of the Abeta peptide modulate its tendency to form insoluble protofibrils and fibrils (25, 26).

Senile plaques vary in protein composition, both in terms of the types of Abeta peptides and of other proteins found in the plaques. Monomeric Abeta peptides are 39 to 43 amino acids in length and occur in two major forms: Abeta1-42 and Abeta1-40 (2, 22, 27). The N terminus of Abeta peptides is known to be heterogeneous. In senile plaques, the predominant N-terminal-truncated Abeta peptides are Abeta3-40/42, Abeta11-40/42, and Abeta17-40/42 (P3) (28-31). In addition to Abeta, other proteins accumulate within senile plaques, including apolipoprotein E (apoE), {alpha}2-macroglobulin, interleukin-1{alpha}, interleukin-6, components of the complement system, the {alpha}2-macroglobulin receptor/low-density lipoprotein receptor-related protein, and collagenous Alzheimer amyloid component/collagen XXV (32-38). The APOE {epsilon}4 allele is associated with an increased risk for AD and represents the major genetic risk factor for sporadic AD [see Raber Review and (39)]. In addition, apoE binds Abeta and is capable of forming apoE-Abeta complexes (40, 41).

Senile plaques associate with neuronal processes and different types of cells. Neuritic plaques often consist of Abeta deposits associated with dystrophic neurites that show abnormal tau ({tau}) protein (1, 42-45). Moreover, diffuse and cored plaques can be associated with amyloid precursor protein (APP) and chromogranin-A-positive dystrophic neurites, reactive astrocytes, and microglial cells (42, 43, 45-48). In cases with concurrent Parkinson's disease (PD) or Lewy body disease, dystrophic neurites in neuritic plaques can contain Lewy neurite-like {alpha}-synuclein aggregates (49, 50). {alpha}-synuclein (which aggregates in PD), however, is not present in plaques in pure sporadic AD cases (51). Determining the morphology, as well as the protein and cellular components, of senile plaques permits differentiation of plaque types (Fig. 1 and supplementary data). Although different authors (3, 5, 42, 44, 52-54) use different plaque classification schemes, the classification suggested in Fig. 1 covers most of the plaque types described to date in the literature (see also supplementary data).

Figure 1
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Fig. 1. Major plaque types in the human brain. (A to D) show diffuse plaques not exhibiting N-terminal epitopes of Abeta; they are sharply delineated diffuse plaques that can be immunolabeled with antibodies directed against Abeta1-42 (A). They frequently colocalize apoE (B and C) but do not exhibit N-terminal epitopes of Abeta such as AbetaN1D (D). They often occur in areas newly involved in Abeta deposition. (E to G) show a second type of diffuse plaques that can occur in regions newly involved in Abeta deposition. They are sharply delineated diffuse plaques exhibiting C- and N-terminal epitopes of Abeta [(E) and (F)] but not apoE (G). Arrows indicate the plaques in Abeta42 and Abeta1-17-stained sections [(E) and (F)], whereas plaques remain unstained in the apoE-stained section (G). Only neurofibrillary tangles are weakly immunolabeled [arrowheads in (G)]. (H to J) show a third type of sharply delineated plaques that contain C- and N-terminal epitopes of Abeta [(H) and (I)], as well as apoE (J). This type of plaque is frequently seen in areas newly involved in Abeta deposition in individuals homozygous for the APOE allele {epsilon}4 (APOE {epsilon}4/4), which is a major risk factor for AD. (K to O) show fleecy amyloid plaques, a form of diffuse plaques that consist of indistinctly bordered clouds of Abeta. These Abeta clouds are Abeta42-positive and often colocalize with apoE (K, L, and O), although antibodies directed against N-terminal epitopes of Abeta, such as AbetaN1D, do not stain this plaque type (72) [(M) and (N)]. Fleecy amyloid is associated with increased numbers of Abeta-containing astrocytes [arrows in (O)]. APP-type diffuse neuritic plaques (P) show Abeta deposits associated with swollen APP-positive dystrophic neurites, whereas paired helical filament (PHF)-type diffuse neuritic plaques (Q and R) are characterized by the presence of dystrophic neurites containing neurofibrillary material that is detectable with the Gallyas silver method [black-stained neurites in (Q)] and with antibodies raised against abnormal {tau} protein, such as TG3 (114; gift from P. Davies) [arrows in (R)]. These plaques are associated with activated, CD68-positive microglial cells [blue-black stained cells in (R)] and with astrocytes that exhibit glial fibrillary acidic protein (GFAP) [reddish-stained cells in (R)]. The subpial band-like amyloid (S) and the presubicular lake-like amyloid (T) are region-specific plaque types that display a morphological pattern similar to that of diffuse Abeta deposits. Abeta-containing astrocytes are associated with the subpial band-like amyloid [arrows in (S)]. PHF-type cored neuritic plaques (U) are characterized by a central, compact amyloid core surrounded by a halo consisting of diffuse Abeta deposits. These plaques are associated with dystrophic neurites that contain neurofibrillary material, which can be detected by the Gallyas silver method. {alpha}-synuclein-type diffuse neuritic plaques (also referred to as Lewy plaques) are characterized by {alpha}-synuclein-immunolabeled dystrophic neurites (V) (50). These plaques tend to occur as clusters in the neuropil or in the vicinity of small blood vessels, particularly in the mesocortex and hippocampal formation. Core-only plaques (W) consist of pure amyloid cores not associated with diffuse amyloid deposits or reactive changes. White matter plaques can be subdivided into diffuse (X) and globular type (Y). Calibration bar: (A to D, and K to N) 30 µm; (E to G, and T) 250 µm; (H to J) 40 µm; (O to S, U, and V) 60 µm; (W to Y) 90 µm. [(E to N) are reproduced from (71) with permission from Acta Neuropathologica; (O, Q, and T to Y) from (53) with permission from the Journal of Neuropathology and Experimental Neurology; and (V) from (50) with permission from Landes Bioscience.]

Phases of Abeta Deposition

Our group has suggested that the distribution of Abeta deposits changes with time and reflects the time course of the expansion of Abeta pathology in the brain. Senile plaque pathology begins with the first diffuse plaques in the neocortex and extends hierarchically into further brain regions (8, 53). In the second phase of Abeta pathology, plaques occur in allocortical areas, such as the entorhinal region, and in the subiculum/CA1 region. In the third phase, the basal ganglia, the thalamus, and the hypothalamus become involved, followed, in the fourth phase, by the midbrain and the medulla oblongata, the portion of the lower brain stem that transmits signals to the spinal cord and is involved in various vital functions. Finally, in a fifth phase, senile plaques develop in the region of the brain stem between the midbrain and the medulla oblongata (the pons) and a part of the brain (cerebellum) involved in movement control. Figure 2 shows the expansion of senile plaque pathology in the medial temporal lobe (53). Thus, the medial temporal lobe pathology permits the distinction of the first four phases but does not allow differentiation between phases 4 and 5.

Figure 2
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Fig. 2. Phases in the expansion of Abeta deposition in the medial temporal lobe (MTL). Abeta deposition begins in phase 1 in the temporal neocortex; in phase 2, it expands into the subiculum/CA1 region and layers pre-beta, pre-{gamma}, pri-{alpha}, pri-beta, and pri-{gamma} of the entorhinal cortex; in phase 3, it involves the white matter, parvopyramidal layer of the presubicular region, and molecular layer of the dentate fascia, temporal cortex, and entorhinal cortex; and, finally, in phase 4, Abeta deposition is seen into CA4 and the pre-{alpha} layer of the entorhinal region. Different types of senile plaques are located in distinct anatomical regions: Neuritic plaques occur mainly in layers III and V of the neocortex, pre-beta, pre-{gamma}, pri-{alpha}, and pri-beta of the entorhinal cortex, the pyramidal cell layer of the hippocampal formation and subiculum, and the molecular layer of the fascia dentata (5, 42, 90, 114). Fleecy amyloid is restricted to the internal entorhinal layers and the subiculum/CA1 region (70). Band-like amyloid is confined to the subpial part of the temporal and entorhinal molecular layers. Lake-like amyloid is seen only in the parvopyramidal layer of the subiculum (54, 85, 87). (A) shows the distribution of Abeta deposits throughout the Abeta phases in the hippocampal formation at the level of the anterior limit of the dentate gyrus. (B) shows the distribution at the level of the lateral geniculate body. Arrows indicate areas that are newly involved in Abeta deposition in a given phase. DP, diffuse plaque; DNP, diffuse neuritic plaque; CP, cored plaque; CNP, cored neuritic plaque; COP, core-only plaque. [Reproduced from (53) with permission from the Journal of Neuropathology and Experimental Neurology.]

The distinction of the phases of beta amyloidosis (that is, the deposition of Abeta) can be determined based on sections from the medial temporal lobe, providing a good picture of AD-related Abeta pathology without time-consuming studies of the entire brain. This step-by-step involvement of brain regions in Abeta pathology can be used to plot a time course of Abeta deposition in the brain and possibly divide the process into distinct stages. Two arguments strongly support this hypothesis: (i) a similar hierarchical involvement of the same brain regions has been found with Abeta deposition in individuals with Down syndrome and in APP transgenic mice with advancing age (Fig. 3) (30, 55-58); and (ii) the expansion of Abeta deposits correlates with that of NFTs, the frequency of neuritic plaques, and the development of cognitive deficits (8, 59).

Figure 3
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Fig. 3. Abeta deposition in APP-transgenic mice expands into additional brain regions with increasing age. (A) Three-month-old APP23 mice overexpressing APP with the Swedish mutation 670/671 KM -> NL through a Thy-1 promoter (115) do not show Abeta deposits. (B) Abeta deposition begins in female APP23 mice at 5 months of age in the neocortex (boxed area). Here, the first amyloid plaques can be identified (inset). (C) At 11 months of age, allocortical areas, such as the hippocampus, exhibit Abeta plaques (arrow), in addition to neocortical areas. However, the basal ganglia and the thalamus do not show plaques at this stage. (D) Fifteen-month-old female APP23 mice form Abeta plaques in the basal ganglia (striatum; arrows, boxed area). The inset indicates the diffuse nature of these plaques. (E) Abeta deposits in the brain stem occur in mice 26 months of age (arrows, boxed area). The inset shows the diffuse nature of these plaques. Calibration bar: (A to D) 730 µm; (E) 360 µm; insets in (B to E) 25 µm.

The morphologically heterogeneous pattern of senile plaques in different brain regions (3, 53) suggests that region-specific factors contribute to the morphology of senile plaques. However, some plaque types, such as cored and neuritic plaques, only occur in later stages of Abeta deposition and not in regions involved for the first time in the process, whereas diffuse types of plaques occur in all phases of Abeta deposition. Therefore, we speculated that cored and neuritic plaques represent "mature" forms of plaques that developed from diffuse plaques (3, 52). An alternative explanation for the late development of cored and neuritic plaques is that these lesions only form in a brain region that is already altered, whereas diffuse plaques represent Abeta deposition in previously "healthy" areas. The location of neuritic plaques only in regions receiving input from NFT-bearing neurons (53, 60, 61) supports this hypothesis.

Development of Senile Plaques

Analysis of the morphology and location of different types of plaques may provide clues as to how they developed. The development of senile plaques commences when Abeta aggregates in the brain and begins to form fibrils (62). A prerequisite for the deposition of fibrillar Abeta is an increased concentration of Abeta in the brain owing to increased Abeta production or reduced degradation (63). Increased secretion of Abeta occurs in familial AD patients carrying mutations in the APP gene or in the genes encoding the {gamma}-secretase components presenilin 1 and presenilin 2 (62-64). Sporadic AD cases, however, do not show signs of increased production of Abeta, and it has been suggested that reduced cellular degradation of Abeta by neprilysin and insulin-degrading enzyme (63, 65-68) and reduced perivascular drainage (69) may explain the increase in Abeta in the brains of these patients.

The first senile plaques occur in the neocortex and morphologically represent diffuse plaques (4, 8, 53, 70). Similarly, diffuse plaques and/or "fleecy" amyloid occur in other areas of the brain during phases of Abeta deposition when these regions first become involved in senile plaque pathology (53). At later phases of Abeta deposition, which affect areas of the brain previously involved in beta amyloidosis, other plaque types characteristic for these brain regions, such as neuritic plaques and cored plaques, also develop (53) (Fig. 4). Several arguments discussed in the previous section support the hypothesis that the step-by-step involvement of different brain regions represents the time course of Abeta deposition in the brain. It is then possible that plaques evolving in an area that is involved for the first time in a given phase of Abeta deposition are newly formed.

Figure 4
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Fig. 4. Development of senile plaques. Schematic representation of the morphological appearance of Abeta deposits and Gallyas-positive neuritic plaques in area 36, in the entorhinal cortex, CA1, CA4, the subiculum, the parvopyramidal layer of the pre-, para- and transsubiculum (presubiculum), the outer (OML) and inner (IML) portions of the molecular layer of the fascia dentata, and the subpial zone of the neocortex of area 36. The changes in the plaque pattern with higher phases of beta amyloidosis in the medial temporal lobe are displayed. Diffuse plaques occur in regions involved in beta amyloidosis for the first time, whereas cored and neuritic plaques are found in later stages. Only in the CA4 sector is it impossible to distinguish "newly formed plaques" and plaques formed in later stages, because this region is the last to be involved in beta amyloidosis in the medial temporal lobe. DP, diffuse plaques; CP, cored (classical) plaques; COP, core-only plaques; DNPs/CNPs, diffuse and/or cored neuritic plaques). [Reproduced from (53) with permission from the Journal of Neuropathology and Experimental Neurology.]

Five different types of plaques that occur in regions not previously exhibiting Abeta deposits can be distinguished based on their immunohistochemical-staining pattern (Fig. 1 and supplementary data). All five are always non-neuritic in nature and can be detected with the Campbell-Switzer silver technique, indicating the presence of small amyloid fibrils within the plaques (71, 72). These plaques most frequently do not exhibit compact fibrillar amyloid detectable with the Congo-red or the thioflavin-S staining methods (3). N-terminal truncated Abeta has also been described in plaques of young Down syndrome patients and in presumed initial plaques of AD patients (28, 30, 31, 71-76) (Fig. 1). Because senile plaques that occur in a region when it first becomes involved in Abeta deposition are frequently negative for N-terminal epitopes of Abeta and often colocalize with apoE, and because apoE is capable of binding Abeta at amino acids 12 to 28 (40, 77), it is possible that apoE-Abeta complexes in these plaques conceal N-terminal epitopes of Abeta (71). Thus, apoE-Abeta complexes may play a critical role in the initiation of Abeta deposition. A couple of findings support this hypothesis: (i) PDAPP+/+;apoE–/– mice--which overexpress human APP harboring the London mutation (V717F), do not express endogenous apoE, and develop Abeta deposits--exhibit fewer senile plaques than do PDAPP+/ +;apoE+/ + mice (78); and (ii) blocking the Abeta binding site of apoE reduces the number of plaques deposited in the brains of APPK670N/M671L/PS1M146L double-transgenic mice, which overexpress human APP harboring the Swedish mutation (KM670/671NL) and human PS1 harboring the M146V mutation, and develop Abeta deposits (77). Nevertheless, Abeta deposition in PDAPP+/+;apoE-/- mice (78), as well as human autopsy cases that exhibit "newly" formed plaques negative for apoE (71), indicate that although apoE is an important promoter of Abeta deposition, other mechanisms are capable of initiating the process.

Senile plaques that occur in a specific region for the first time in a given phase of beta amyloidosis are not associated with activated astrocytes or microglial cells (79, 80). However, fleecy amyloid plaques, as well as early Abeta deposits in the subpial zone of the molecular layer (the part of the cerebral cortex that borders the leptomeninges) and "vanishing diffuse plaques," are associated with astrocytes that contain Abeta (Figs. 1 and 4) (81-83). These astrocytes differ morphologically from activated astrocytes (81-83) and are thought to take up Abeta from the extracellular space (81, 82, 84). In later phases of beta amyloidosis, "vanishing diffuse plaques" and fleecy amyloid plaques, as well as Abeta-positive astrocytes, disappear and other plaque types are found in these brain areas (72, 81, 82) (Fig. 4).

Plaques found in regions of the brain involved in an earlier phase of Abeta deposition are a heterogeneous group that include cored, cored neuritic, diffuse, diffuse neuritic, core-only, and white matter plaques, as well as presubicular lake-like amyloid and subpial band-like amyloid (Fig. 1) (3, 5, 42, 43, 52-54, 85). Some of these plaque types--subpial band-like amyloid, presubicular lake-like amyloid, white matter plaques of the diffuse type, and diffuse plaques positive for C- and N-terminal antibodies against Abeta and apoE--do not differ morphologically from plaques found in areas not previously involved in beta amyloidosis. On the other hand, other types of plaques--diffuse neuritic plaques, cored plaques, cored neuritic plaques, core-only plaques, and white matter plaques of the globular type--are morphologically distinct (42, 52, 53, 79). These plaque types contain Abeta1-40/42, as well as N-terminal truncated forms such as Abeta3-40/42 and Abeta11-40/42, and, in later stages, Abeta17-40/42 (28-31, 73, 75, 76, 79, 86). Moreover, they contain Congo-red and thioflavin-S-positive compact amyloid fibrils (3).

Diffuse and cored neuritic plaques exhibit APP- and chromogranin-A-positive dystrophic neurites with or without abnormal {tau}-protein aggregates (45, 48). Cored, cored neuritic, and diffuse neuritic plaques predominantly occur in layers III and V of the neocortex and in the hippocampal subfields (5, 6, 42, 44) but not in the basal ganglia, cerebellum, or presubicular region (74, 87-90). Diffuse and cored neuritic plaques with {tau}-containing dystrophic neurites occur only in regions that receive input from NFT-bearing neurons (53, 60, 61). This finding raises the question of whether aberrant sprouting of NFT-bearing neurons is responsible for the development of such neuritic plaques. This hypothesis receives support from the work of Phinney et al. (91), who found that plaques associated with dystrophic neurites in APP transgenic mice result from aberrant sprouting. Additional support comes from the finding that APP-positive dystrophic neurites in neuritic plaques of AD cases have neurofibrillary, abnormal {tau}-protein-containing material (92). Finally, the protein {alpha}-synuclein can be detected in neuritic plaque-associated dystrophic neurites when PD-related Lewy pathology coexists in the AD brain (50), and these dystrophic neurites may represent aberrant sprouting of Lewy pathology-containing neurons.

Cored, cored neuritic, and diffuse neuritic plaques are usually associated with activated microglial cells and astrocytes (33, 46, 47, 52) (Figs. 3 and 4). The presence of reactive astrocytes and microglial cells in these plaques may indicate cellular clearance of Abeta within senile plaques (68, 84, 93). Such mechanisms may be responsible for the observed dynamics of Abeta deposition and senile plaque clearance in APP transgenic mice, when senile plaques are viewed with two-photon imaging for several weeks in living animals (94).

Core-only plaques are found during the late stages of beta amyloidosis and display only a remnant of a cored plaque (52). Such plaques, however, are not seen in every region that contains cored plaques (53). They occur most frequently in the cerebellum, basal ganglia, and hippocampal sector CA4 (53, 95-97) but are not the main type of plaques in these regions (53, 95, 96).

Intracellular and Extracellular Abeta

Neurons express APP and produce Abeta; thus, Abeta can be detected within neurons (98, 99). The accumulation of intraneuronal Abeta in APP transgenic mice shortly before the onset of Abeta deposition suggests that intraneuronal Abeta accumulation precedes the aggregation and deposition of Abeta (100, 101). Moreover, the detection of intracellular Abeta oligomers in dystrophic neurites provides further evidence that, indeed, intraneuronal aggregates may be substantially involved in Abeta toxicity (102, 103). However, transgenic mice that secrete Abeta42 expressed by a BRI-Abeta42-construct, which allows APP-independent production of Abeta42, do not accumulate Abeta42 intracellularly, but form senile plaques (104), suggesting that extracellular Abeta42 is capable of inducing plaque formation (105). This conclusion is supported by the finding that Abeta plaques occur in portions of wild-type brain transplanted into the brains of APP transgenic mice (106). Moreover, Abeta deposits in the blood vessels of the leptomeninges of APP transgenic mice, in which APP is overexpressed by a neuron-specific promoter (107), suggest that diffusion of parenchymal Abeta into the perivascular spaces is a prerequisite for leptomeningeal Abeta deposition.

Both intracellular and extracellular Abeta appear to have neurotoxic properties (Fig. 5). Monomeric Abeta probably is nontoxic. However, extracellular ADDLs, which represent soluble Abeta oligomers, have neurotoxic properties (108-110). They are also found intraneuronally and may be responsible for neurodegeneration (102). In addition to ADDLs, Abeta forms insoluble Abeta fibrils (2, 24), which appear to induce degeneration of neurites and neurons (111-113). Further studies are needed to determine whether intraneuronal Abeta receives its presumably toxic properties via intraneuronal aggregation of Abeta monomers directly after their production within the cell or following their secretion and reuptake by a cell.

Figure 5
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Fig. 5. Roles of monomeric, oligomeric, and fibrillary Abeta in AD-related pathology. The figure shows the chemical and toxic properties of Abeta monomers, Abeta oligomers, Abeta fibrils, and apoE-associated forms of Abeta. The toxic properties of apoE-linked Abeta forms are not clear.


Abeta deposits result from the accumulation and aggregation of extracellular Abeta. The cause of Abeta accumulation in the extracellular space of the brain is either increased production or dysfunctional Abeta clearance. However, intraneuronal Abeta production is not necessarily a prerequisite for Abeta deposition. Specific regions of the brain become involved in Abeta deposition in a systematic manner. This chronological sequence apparently represents a step-by-step expansion of Abeta deposition into the areas of the brain. Thereby, the formation of ADDLs, Abeta fibrils, and apoE-Abeta complexes appears to be critically involved in the early phases of plaque formation.

March 8, 2006
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  116. The authors wish to express their thanks to I. Szász and H. U. Klatt for graphics and artwork. We also thank M. Staufenbiel (Institute for Biomedical Research, Basel, Switzerland) for reading the manuscript. The authors acknowledge the gift of the TG3 antibody from P. Davies.
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