Brain pathology in three subjects from the same pedigree with presenilin-1 (PSEN1) P264L mutation.

AIMS: Our goal was to assess pathological lesions with respect to type and distribution and to compare these results with the clinical presentation including symptoms and mode of progression in three members of the same pedigree with a P264L presenilin-1 gene mutation. METHODS: We used immunohistochemistry and a tissue microarray technique applied to post mortem brain tissue samples. RESULTS: All three subjects were demented, one subject displayed spastic paraparesis and two had Parkinsonism. All three cases displayed abundant cotton wool plaques composed of amyloid-beta42 but also containing other proteins, for example, hyperphosphorylated tau and in one case TAR DNA binding protein 43. The distribution of the pathology varied and seemed to some extent to be related to the clinical phenotype. An association was detected between neocortical/thalamic involvement and psychiatric symptoms, between striatal/amygdaloid involvement and Parkinsonism, and between brainstem involvement and spastic paraparesis. CONCLUSIONS: Subjects from the same pedigree carrying the same mutation display a clear variability in the type and distribution of pathology as well as in their clinical symptoms. These results emphasize that still unknown factors significantly alter the pathological and clinical phenotypes in genetically predetermined disease.

Projections from the amygdaloid complex to the magnocellular cholinergic basal forebrain in rat.

The amygdaloid complex has a key role in the modulation of behavioral responses in life-threatening situations, including the direction of attentional responses to sensory stimuli. The pathways from the amygdala to the basal forebrain cholinergic system, which projects to the cortex, are proposed to contribute to the modulation. To further explore the topography and postsynaptic targets of these pathways, we investigated the projections from the different divisions of the lateral, basal, accessory basal, and central nuclei of the amygdala to the cholinergic basal forebrain in rat using a sensitive anterograde tracer, Phaseolus vulgaris leucoagglutinin. The most substantial projections from the amygdala to the basal forebrain are directed to the ventrolateral and dorsomedial aspects of the substantia innominata and the fundus of the striatum. The heaviest projections originate in the capsular, lateral, and intermediate divisions of the central nucleus as well as in the magnocellular and parvicellular divisions of the basal nucleus. Light microscopic analysis of double-stained preparations revealed that the distribution of amygdaloid efferents and cholinergic neurons overlaps most prominently in the ventrolateral substantia innominata. Despite the fact that the central nucleus efferents and cholinergic elements overlap in the ventrolateral substantia innominata, electron microscopic analysis revealed, first, that the postsynaptic targets of the central nucleus efferents are non-cholinergic, probably GABAergic, neurons. Second, 80% of the synaptic contacts were symmetric. The present data extend previous observations showing that the different amygdaloid nuclei provide projections to the selective basal forebrain areas. Further, the central nucleus efferents modulate cholinergic neurons in the basal forebrain indirectly via the GABAergic interneurons.

Projections from the lateral, basal and accessory basal nuclei of the amygdala to the perirhinal and postrhinal cortices in rat.

The projections from the amygdaloid complex to the hippocampus and surrounding cortex have a critical role in the formation of memories for emotionally arousing stimuli and in the spread of epileptic seizures. The present study investigated the organization of amygdaloid projections to the perirhinal and postrhinal cortices by injecting the anterograde tracer Phaseolus vulgaris leucoagglutinin into the different subdivisions of the lateral, basal or accessory basal nuclei of the amygdala in rat (n = 53). Analysis of immunohistochemically stained sections indicated that the medial and dorsolateral divisions of the lateral nucleus project heavily to layers I-V of caudal area 35 and to layers I-III of the rostroventral postrhinal cortex. The dorsolateral division also moderately innervates layer I of caudoventral area 36. The magnocellular division of the basal nucleus projects moderately to layers V and VI of rostral areas 35 and 36. The parvicellular division of the accessory basal nucleus projects moderately to layer V of caudal area 35, whereas the magnocellular division projects moderately to layers I and II of rostral area 35. Via these substantial, topographically organized projections, the amygdaloid complex might modulate information processing at different levels of the medial temporal lobe memory system.

Interconnectivity between the amygdaloid complex and the amygdalostriatal transition area: a PHA-L study in rat.

The amygdala orchestrates the formation of behavioral responses to emotionally arousing stimuli. Many of these responses are initiated by the central nucleus, which converges information from other amygdaloid nuclei. Recently, we observed substantial projections from the amygdala to the amygdalostriatal transition area, which is located dorsal to the central nucleus. These projections led us to question whether the amygdalostriatal transition area has a role in the initiation of behavioral responses in emotionally arousing circumstances. To explore this anatomically, we traced the interconnections between the amygdalostriatal transition area and the amygdaloid complex using the anterograde tracer Phaseolus vulgaris-leucoagglutinin. The lateral (the medial division and the caudal portion of the dorsolateral division) and the accessory basal nuclei (the parvicellular division) provide moderate-to-heavy projections to the amygdalostriatal transition area. Projections back to the amygdala are light and are composed of thin, faintly stained varicose fibers that resemble the labeling of cholinergic terminals. The extra-amygdaloid outputs of the amygdalostriatal transition area are sparse and include moderate projections to the caudoventral globus pallidus, the ansa lenticularis, and the substantia nigra pars lateralis. These data suggest that the amygdalostriatal transition area is one of the major targets for projections originating in the lateral and accessory basal nuclei of the amygdala. Via these pathways, emotionally significant stimuli can evoke behavioral responses that are different from those initiated via projections from the amygdala to the central nucleus. One such candidate response is the orienting response (i.e., saccadic eye movements and head direction) in a pathway that includes a projection from the lateral/accessory basal nucleus of the amygdala to the amygdalostriatal transition area, and from there to the substantia nigra, pars lateralis.

Reciprocal connections between the amygdala and the hippocampal formation, perirhinal cortex, and postrhinal cortex in rat. A review.

Recent anterograde and retrograde studies in the rat have provided detailed information on the origin and termination of the interconnections between the amygdaloid complex and the hippocampal formation and parahippocampal areas (including areas 35 and 36 of the perirhinal cortex and the postrhinal cortex). The most substantial inputs to the amygdala originate in the rostral half of the entorhinal cortex, the temporal end of the CA1 subfield and subiculum, and areas 35 and 36 of the perirhinal cortex. The amygdaloid nuclei receiving the heaviest inputs are the lateral, basal, accessory basal, and central nuclei as well as the amygdalohippocampal area. The heaviest projections from the amygdala to the hippocampal formation and the parahippocampal areas originate in the lateral, basal, accessory basal, and posterior cortical nuclei. These pathways terminate in the rostral half of the entorhinal cortex, the temporal end of the CA3 and CA1 subfields or the subiculum, the parasubiculum, areas 35 and 36 of the perirhinal cortex, and the postrhinal cortex. The connectional data are summarized and the underlying principles of organization of these projections are discussed.

Projections from the lateral, basal, and accessory basal nuclei of the amygdala to the hippocampal formation in rat.

The amygdaloid complex and hippocampal formation mediate functions involving emotion and memory. To investigate the connections that regulate the interactions between these regions, we injected the anterograde tracer Phaseolus vulgaris-leucoagglutinin into various divisions of the lateral, basal, and accessory basal nuclei of the rat amygdala. The heaviest projection to the entorhinal cortex originates in the medial division of the lateral nucleus which innervates layer III of the ventral intermediate and dorsal intermediate subfields. In the basal nucleus, the heaviest projection arises in the parvicellular division and terminates in layer III of the amygdalo-entorhinal transitional subfield. In the accessory basal nucleus, the parvicellular division heavily innervates layer V of the ventral intermediate subfield. The most substantial projection to the hippocampus originates in the basal nucleus. The caudomedial portion of the parvicellular division projects heavily to the stratum oriens and stratum radiatum of CA3 and CA1. The accessory basal nucleus projects to the stratum lacunosum-moleculare of CA1. The subiculum receives a substantial input from the caudomedial parvicellular division. The parasubiculum receives dense projections from the caudal portion of the medial division of the lateral nucleus, the caudomedial parvicellular division of the basal nucleus, and the parvicellular division of the accessory basal nucleus. Our data show that select nuclear divisions of the amygdala project to the entorhinal cortex, hippocampus, subiculum, and parasubiculum in segregated rather than overlapping terminal fields. These data suggest that the amygdaloid complex is in a position to modulate different stages of information processing within the hippocampal formation.

A time-resolved immunofluorometric assay of sialyl Lewis x-degrading alpha 2,3-sialidase activity.

We have developed an assay for alpha 2,3-sialidase (EC 3.2.1.18) which employs a biotinylated carbohydrate-polyacrylamide conjugate as substrate for the enzyme. The solution-phase sialidase reactions are followed by a selective capture of biotinylated neoglycoconjugates onto a microtitration plate coated with streptavidin. The amount of the reaction product formed is then rapidly and easily quantified using a product-specific primary antibody and europium chelate-labeled secondary antibody. This method combines the advantages of solution-phase enzymatic reaction and suitability for high-throughput screening typical of solid-phase assays. The assay gives a detectable signal with 0.4% of substrate sites desialylated. We have demonstrated the utility of the assay by measuring alpha 2,3-sialidase activity from crude lysates of cultured rat endothelial cells by using biotinylated sialyl Lewis x glycoconjugate as substrate. Endothelial sialidase(s) showed up to 250-fold higher activity toward soluble compared to immobilized substrate. Product formation detected with an anti-Lewis x antibody was linear in the range of 0.1-4 micrograms/ml of protein in endothelial cell lysate. High sensitivity of the assay was achieved by using solution-phase enzyme reaction and time-resolved fluorometric detection. The same assay format used here is easily adapted to detect activities of several different glycosidases or glycosyl-transferases by using appropriate substrates and antibodies.