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aALS occurs as a familial or sporadic disease. Approximately 5-10% of all ALS cases are familial. Themajority of cases are sporadic, with no yet identified mutations.

bAD occurs as a familial or sporadic disease. Approximately 10% of all AD cases are familial. The majority of AD cases are sporadic.

aALS occurs as a familial or sporadic disease. Approximately 5-10% of all ALS cases are familial. Themajority of cases are sporadic, with no yet identified mutations.

bAD occurs as a familial or sporadic disease. Approximately 10% of all AD cases are familial. The majority of AD cases are sporadic.

Figure 1 Severe atrophy of the brain occurs in Alzheimer's disease. (A) Midsagittal view of the brain from an 86-year-old normal, individual. The cerebral cortex is normal, with broad gyri and narrow sulci. Scale bar = 23 mm (same for B). (B) Midsagittal view of the brain from an 85-year-old individual with Alzheimer's disease. The cerebral cortex is atrophic, as indicated by widening of the sulci and narrowing of the gyri (white arrowheads).

Figure 1 Severe atrophy of the brain occurs in Alzheimer's disease. (A) Midsagittal view of the brain from an 86-year-old normal, individual. The cerebral cortex is normal, with broad gyri and narrow sulci. Scale bar = 23 mm (same for B). (B) Midsagittal view of the brain from an 85-year-old individual with Alzheimer's disease. The cerebral cortex is atrophic, as indicated by widening of the sulci and narrowing of the gyri (white arrowheads).

normally. Pyramidal neurons in the neocortex and hippocampus (Fig. 4A, Table I) are highly vulnerable to the formation of neurofibrillary tangles. Neurofi-brillary tangles are abnormal bundles of protein filaments that occur within neurons (Fig. 4B). These tangled masses consist of paired helical filaments containing t protein (Fig. 4C). Senile plaques are formed throughout the brain parenchyma, and in AD they occur in large numbers (Fig. 4D). The composition of senile plaques is very complex (Figs. 4D and 5), consisting of dystrophic neurites

(damaged and swollen dendrites or axon terminals), activated astrocytes and microglia, and extracellular deposits of insoluble amyloid. Amyloid occurs as fibrils composed of a small peptide (Ab) consisting of 40-42 amino acid residues. This abnormal protein fragment is derived proteolytically from the amyloid precursor protein (APP), a cell surface protein. APP may participate directly in the pathogenesis of AD because mutations have been identified in the APP gene that are linked to early-onset AD in some families (Table II).

Figure 2 The synaptic vesicle cycle may be abnormal in Alzheimer's disease. (A) Electron micrographs of synapses in the cerebral cortex of a rhesus monkey. Axon terminals (T), containing many small clear synaptic vesicles (arrowheads), from synapses (open arrow) with postsynaptic structures. Synaptic vesicles cluster at the active zone of the presynaptic membrane. The narrow space between the presynaptic and postsynaptic components is the synaptic cleft. Scale bar = 1.0 mm. (B) Diagram of the synaptic vesicle cycle. This cycle functions in the regulated release of neurotransmitter-containing vesicles (filled circles) from the presynaptic terminal. Abbreviations: Az, synaptic active zone; Sc, synaptic cleft. The synaptic vesicle cycle can be divided into six major components, as indicated. Some of the specific proteins that function at each phase of the cycle are indicated. Some of these proteins (indicated by the asterisk) appear to be selectively vulnerable in individuals with Alzheimer's disease.

Figure 2 The synaptic vesicle cycle may be abnormal in Alzheimer's disease. (A) Electron micrographs of synapses in the cerebral cortex of a rhesus monkey. Axon terminals (T), containing many small clear synaptic vesicles (arrowheads), from synapses (open arrow) with postsynaptic structures. Synaptic vesicles cluster at the active zone of the presynaptic membrane. The narrow space between the presynaptic and postsynaptic components is the synaptic cleft. Scale bar = 1.0 mm. (B) Diagram of the synaptic vesicle cycle. This cycle functions in the regulated release of neurotransmitter-containing vesicles (filled circles) from the presynaptic terminal. Abbreviations: Az, synaptic active zone; Sc, synaptic cleft. The synaptic vesicle cycle can be divided into six major components, as indicated. Some of the specific proteins that function at each phase of the cycle are indicated. Some of these proteins (indicated by the asterisk) appear to be selectively vulnerable in individuals with Alzheimer's disease.

The functions of APP are still not well-defined, although it appears that APP functions at synapses. APP is an abundant and ubiquitous protein within CNS and other tissues. APP has structural features similar to some cell surface receptors and may be a G-protein-coupled receptor. Secreted and nonsecreted forms of APP exist, with different APP derivatives having neurotrophic or neurotoxic actions. APP is incorporated into the extracellular matrix and, thus, may have roles in cell-cell and cell-substrate adhesion. Furthermore, APP may function in the regulation of neurite outgrowth, perhaps by modulating the effects of neurotrophins and cytokines in the responses of neurons and glia to brain injury.

In cell culture, APP normally undergoes constitutive proteolytic cleavage by an a-secretase. This enzyme cleaves APP within the Ab region at or near the plasma membrane, thereby generating secreted forms of APP and precluding the formation of full-length Ab peptide fragments. APP is also metabolized by an endosomal-lysosomal pathway that, unlike the a-secretase pathway, yields amyloidogenic fragments of Ab that are deposited in senile plaques (Fig. 4D). Ab can be formed normally in vivo and in vitro, and studies of

Figure 3 Synapses in the hippocampus of individuals with Alzheimer's disease are abnormal. (A) The hippocampus of normal, aged control humans has very high levels of synapses, as revealed by the synaptic vesicle protein synaptophysin (the intensity of the black staining reflects the amount of synaptophysin immunoreactivity). Scale bar = 42 mm (same for B). (B) The hippocampus of an individual with Alzheimer's disease shows a marked depletion of synaptophysin immunoreactivity (as reflected by the less intense black staining).

Figure 3 Synapses in the hippocampus of individuals with Alzheimer's disease are abnormal. (A) The hippocampus of normal, aged control humans has very high levels of synapses, as revealed by the synaptic vesicle protein synaptophysin (the intensity of the black staining reflects the amount of synaptophysin immunoreactivity). Scale bar = 42 mm (same for B). (B) The hippocampus of an individual with Alzheimer's disease shows a marked depletion of synaptophysin immunoreactivity (as reflected by the less intense black staining).

cultured human cells and aged non-human primates show that it is generated intracellularly.

Although Ab has been shown to be neurotoxic in cell culture, a causal role for Ab in neuronal degeneration within the brain remains speculative. A b-secretase cleaves APP at the N-terminus of Ab, and a g-secretase cleaves APP at the C-terminus of Ab, causing the formation of Ab that is either 40 or 42 amino acids long. This pathway for APP metabolism is found within the endoplasmic reticulum and Golgi apparatus of neurons. Mutant presenilins (Table II) promote Ab42 generation. Presenilins, which are present at relatively low levels in the brain, localize to the endoplasmic reticulum and Golgi apparatus. Mutant presenilin is processed differently from normal pre-senilin, and fragments that are normally subject to endoproteolytic cleavage tend to accumulate. Thus, metabolism of APP through the b- and g-secretase pathways may be promoted by presenilin-1 and presenilin-2 gene mutations linked to early-onset familial AD (Table II).

We and others have shown that APP is present in essentially all neurons and in some astroglia, micro-glia, and vascular endothelial cells. The most prominent neuronal localization of APP is within cell bodies and dendrites and is particularly enriched postsynap-tically at some synapses. The expression of APP in nonneuronal cells in the brain is low in comparison to the dominant expression of APP within neurons and their processes. It appears that astroglia and microglia constitutively express APP at low levels in the resting state. However, the relative enrichment of APP within these neuroglial cells changes in response to brain injury and synaptic abnormalities. This idea is supported by our finding that APP is expressed prominently by activated astroglia and microglia within senile plaques of aged nonhuman primates and by other reports showing that APP is localized to

Figure 4 Neurofibrillary tangles and amyloid deposits are brain lesions that are formed in patients with Alzheimer's disease. (A) Pyramidal neurons in the neocortex (arrows) are vulnerable in individuals with Alzheimer's disease. Scale bar = 50 mm. (B) Neurofibrillary tangles, which are abnormal intracellular aggregates of protein (arrows), are formed in pyramidal neurons in patients with Alzheimer's disease. Scale bar = 50 mm. (C) Neurofibrillary tangles are composed of t proteins (arrows). Scale bar = 100 mm. (D) Individuals with Alzheimer's disease form numerous abnormal extracellular deposits of Ab amyloid protein in the brain (arrows). Scale bar = 200 mm.

Figure 4 Neurofibrillary tangles and amyloid deposits are brain lesions that are formed in patients with Alzheimer's disease. (A) Pyramidal neurons in the neocortex (arrows) are vulnerable in individuals with Alzheimer's disease. Scale bar = 50 mm. (B) Neurofibrillary tangles, which are abnormal intracellular aggregates of protein (arrows), are formed in pyramidal neurons in patients with Alzheimer's disease. Scale bar = 50 mm. (C) Neurofibrillary tangles are composed of t proteins (arrows). Scale bar = 100 mm. (D) Individuals with Alzheimer's disease form numerous abnormal extracellular deposits of Ab amyloid protein in the brain (arrows). Scale bar = 200 mm.

astrocytes in senile plaques in cases of AD. Other studies have shown that some forms of APP are expressed in reactive astrocytes in the early stages of brain damage. Because levels of APP in some neurons and nonneuronal cells are increased by the cytokine interleukin-1, it is likely that the expression of APP is inducible in glia when these cells are activated in response to neuronal injury.

Several theories for the formation of senile plaques and Ab deposits have been presented. The genesis of senile plaques may begin with the abnormal processing of APP via b-secretase and the formation of extracellular Ab before the degeneration of cellular elements within these brain lesions. Alternatively, Ab may be derived from degenerating axonal nerve terminals or dendrites containing APP that evolve into neurite-rich foci that form Ab at the cell plasma membrane by aberrant processing of APP within neurons. In addition, invading reactive microglia and astroglia as well as capillaries may actively produce Ab from APP.

We have found that senile plaques are dynamic brain lesions that evolve from early defects in synapses within the neuropil to mature plaques and extracellular deposits of Ab (Figs. 4D and 5). The staging of these lesions is thought to be the degeneration of neuritic structures, followed by the attraction of reactive glia and the subsequent deposition of extracellular Ab derived from microglia or astrocytes. Studies demonstrate that structural and biochemical perturbations within neuronal and nonneuronal cells, importantly glia, occur before the deposition of extracellular Ab fibrils. Furthermore, these results suggest that focal abnormalities in synaptic contacts within the neuropil (synaptic disjunction) may instigate this complex series of events resulting in the formation of diffuse senile plaques and deposits of Ab (Figs. 4D and 5). In

Figures Electron microscopy reveals the complexity of the senile plaques that are formed in the cerebral cortex. Extracellular amyloid (A) is surrounded by numerous dystrophic, swollen neurites (dn), which are filled with abnormal membranous organelles. Microglia (m) infiltrate into the plaques. A nearby neuron (N) appears structurally normal Scale bar = 4 mm.

Figures Electron microscopy reveals the complexity of the senile plaques that are formed in the cerebral cortex. Extracellular amyloid (A) is surrounded by numerous dystrophic, swollen neurites (dn), which are filled with abnormal membranous organelles. Microglia (m) infiltrate into the plaques. A nearby neuron (N) appears structurally normal Scale bar = 4 mm.

response to synaptic disjunction in the aged brain, astroglia and microglia produce AjS. The molecular pathology we and others have identified at the synaptic level in humans with AD (Figs. 2 and 3)

may be related to senile plaque lesions and Ab deposits (Figs. 4D and 5). Defects in the synaptic vesicle cycle (Fig. 2) and synaptic disjunction in the neuropil may lead to abnormal APP processing within neuroglia and could be early events in the formation of senile plaques and Ab lesions.

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