• AGING and DEMENTIAS

• Canonical changes during aging• Classification of dementias• Symptoms of dementia

• ALZHEIMER'S DISEASE• Clinical manifestations • Cellular pathology • Cholinergic deficits, relationship between cholinergic loss,

pathological lesions and dementia• Other neuropathological-neurochemical abnormalities• Progression of the disease• Pathology of the aging brain in relation to AD• Clinical-pathological correlations• Aethiology and pathogenesis• Therapy in AD

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From Adams and Victor, 1993

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a: Diffuse β-amyloid deposits in the frontal cortex stained with monoclonal antibody 4G8 x 50. Braak and Braak

b: Primitive plaque without central amyloid core or dystrophic neurites. Modified Bielschowsky silver stain x 200. Braak and Braak.

c: Classical plaque with central amyloid core and peripheral crown of dystrophic neurites. Modified Bielschowsky stain x 200 . Braak and Braak.

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a: forms of extracellular BA protein deposits. b: neuritic plaques, tangles and neuropil threads. c: first traces of tangle material, d: the mature tangle fills the cell body, e: extraneuronal ‘ghost’, f-m: neurofibrillary tangles in different cell types of the hippocampus, n: tangle-bearing isocortical layer IIIab-pyramidal cell, o: ghost tangle in CA1. Silver technique. Braak and Braak.

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a: Jellinger, 1990; Mioyoshi and Sato, 1991; b : Manns et al., 1991; c: Masliah et al., 1991; d: Xuereb et al., 1991

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Maps of rostro-caudal cholinergic neurons (stained with the antibodsy against choline acteyltransferase) in serial 40 um coronal sections of the basal forebrain in human. Ch1-Ch4 nomenclature according to Mesulam. From Lehericy et al. 1999

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Maps of coronal sections in the human brain. ChAT staining. From Lehericy et al

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Summary of the major pathways for cholinergic innervation of the cortical mantle by the magnocellular basal complex (Saper, 1990).

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(Geula and Mesulam, 1994)

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Mean density of neuritic plaques in 5 neocortical regions as a function of dementia severity. (Haroutunian et al., 1998)

Median of ratings of neuritic plaque density using the neuropathological battery of the CERAD. 0=absent; 1=sparse; 3= moderate and 5=severe in the hippocampus, entorhinal cortex and amygdala.

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Density of neurofibrillary tangles in four neocortical regions and in the entorhinal cortex, hippocampus and amygdala in non-demented (CDR score 0), questionable ( CDR= 0.5), moderately (CDR=2) and demented (CDR=5) subjects. The y axis represents the median of Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neurofibrillary ratings (0 indicates none; 1 sparse; 3=moderate and 5=severe). (Haraoutuniqan et al., 1999)

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AChE-positive cholinergic fibers in layer III of the auditory assoc. cortex of a 71 year old normal person and of a 67-year old patient with AD. This region displays severe loss of cholinergic neurons, accompanied by a high density of plaques and tangles (NFT).

ACHE-positive cholinergic fibers in LIII of the cingulate cortex of a normal person and of a 67-year old patient with AD. The cingulate cortex shows a remarkable preservation of cholinergic fibres, however, this area contains high density of amyloid plaques and tangles. (Geula and Mesulam, 1994)

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Geual and Mesulam, 1994

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Activity of ChAT in 9 cortical regions as a function of dementia severity. Relative to the group without dementia (CDR score=0), the activity of ChAT was significantly reduced (p<0.001 for all) in the CDR 5.0 group only. BA indicates Brodmann area. (Davis et al., 1999)

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Correlation of ChAT activity in the superior temporal gyrus (Brodmann area 22) with neuirtic plaque density (left chart) and neurofubriallary tangle density (right chart) for the entire cohort. (Davis et al., 1999)

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Thioflavin S-stained neurofibriallary tangles in layer II of the entorhinal cortex in AD. These neurons give rise to major component of the perforant pathway that links the cortex with the dentate gyrus.

Alz-50 terminal immunoreactivity in the outer two thirds of the molecular layer of the dentate gyrus in an area that would correspond to the terminal zone of the perforant pathway. This pattern of immunoreactivity suggests that the AD antigen recognized by Alz-50 is located in the terminals of LII entorhinal neurons. Note the presence of Alz-50 immunoreactive neuritic plaques in the immunoreqactive zone. The vessel marks the location of the hipp. Fissure. The granule cells of the dentate gyrus (SG) have been stained with thopnin.

(G. van Hoesen)

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Distribution of neurofibrillary tangles in the auditory cortex from a case of AD. Note the primary auditory coretx (Brodmann’s area 41 and 42 is largely spared. The dorsal and lateral parts of area 22, the sensory association cortex, are also relatively spared. More distal auditory association areas in the upper bank of the superior temporal sulcus contain extensive pathology (Mesulam)

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Development of neurofibrillary tangles and neuropil threads from transentorhinal to isocortical stages. Increasing density of shading indicates increasing severity of the pathological changes. (Braak and Brrak, 1994)

Neuropathological staging of AD-related changes in the anteromedial portion of the temporal lobe, (Braak and Braak, 1994).

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Summary diagrams of neurofibrillary changes seen in anteromedial portions of the temporal lobe and development of changes from stage I to stage VI of AD. Fd=fascia dentata; gr=granula, mo=molecular layer. CA1: m=molecular; p=pyramidal; o=oriens; a=alveus. (Braak and Braak, 1994)

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Summary diagram of neurofibrillary changes seen in the occipital cortex in stages III-VI of AD. Left, various architectonic schemes to show the laminar pattern in the striate (core), parastriate (belt) and the peristriata association cortex (Braak and Braak, 1994

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Hof and Morrison, 1994

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Simplified diagrams of connections between the isocortex and subcortical ‘centers’ of the motor cortex (a); connections between imortant centers of the ‘limbic’ system (b) and diagram of connections between the isocortex and ascending subcortical modulatory centers (Braak and Braak, 1994).

a b c

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Predilection sites for amyloid deposits (b) and neurofibrillary changes. Compare with Plate 28 for identification of boxes. (Braak and Braak, 1994).

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A: Domain structure and functional map of APP showing location of the BA4 region (shaded). The APP-770 transcipt includes a Kunitz protease inhibitor-motif (from Hardy).

B: Schematic showing the BA domain, residing partially in the transmembrane, partially extracellularly. Note the alfa and Beta-secretase cleavage sites and the positions of APP mutations linked to familial AD. Cleavage at residues 40 and 42 is thought to be the result of the gamma-secretase (from D. Price).

Cell membrane

s APP

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A: APP mutation helix. The relationships between mutation sites and the cleavage sites are indicated. Gray area: membrane (Hardy). B: Schematic drawing showing the cleavage sites of the alfa, Beta and gamma-secretase and the resulting fragments. The left side shows the APP, the right the Notch proteolytic processing. sAPP= soluble APP, CT= C-terminus fragment; Tr sAPP=truncated sAPP; p3=fragment. ANK, LN, EGF = different Notch domains

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Hypothetical scheme to show the APP-metabolite-induced toxicity through the disruption of ionic balance. APP is processed through the

Golgi apparatus and is either (1) metabolized to sAPP, CT and BA fragments and released from the cell or (2) transported to and incorporated into the membrane as full-length APP. (3) APP might be cleaved to release sAPP or (4) might be transported to the endosomes or lysosomes. Intracellular CT fragments and BA might (5) form ion channels in the cell membrane or (6) puncture holes in Ca2+ stores. Both actions could result in ionic imbalance and cell damage (7-8), leading to cell death through apoptosis or necrosis. BA fragments released from the cell could modulate surrounding transportes (10), ionic pump or exchangers (11), receptors (12) ion channels (13) and form de novo ion channels (14). (Fraser et al).

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Notch and APP proteolytic processing. The domain structure of murin Notch 1 and human APP717/770 are indicated. APP and Notch are drawn approximately to scale. The regions that are important for proteolytic processing are magnified and the amino-acid sequences are displayed using the one-letter code. Notch 1 is cleaved in the ectodomain by furin, while APP is cleaved by alfa and B-secretase. Both proteins are cleaved in their transmembrane domain by a gamma-secretase-like activity that is controlled by presinilin. Asterisks indicate the localization of mutations in the APP and preseilin-1 sequence.

Schematic drawing showing the 8 transmembrane domain topology of PS1 (blue), APP (yellow) and Notch 1 (red). The endoproteolytic cleavage site of PS1 is indicated bt red arrow and the proposed crucial aspartates (D257 and D385) are indicated by red dots. The intramembranous clevage sites in APP and Notch 1 are indicated by blue arrows and regions corresponding to carboxyl-terminus fragments (CTF) and the Notch intracellular domain (NICD) are also indicated. Note that APP is cleaved at multiple sites by gamma-secretase, whereas cleavage of Notch 1 occurs at single site. Pink and blue arrows indicate the furin and TACE sites in the Notch 1 ectodomain and black arrows the alfa and Beta secretase sites in the APP ectodomain

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36Cartoon (Science, 294, 1296, 2001) showing that cholesterol secreted by astrocytes bound to large lipoprotein particles containing apoE. These particles are internalized by neurons, leading increased cholesterol within neuronal membranes. Cholesterol is needed to activate signaling pathway that triggers synaptogenesis –either an apoE receptor pathway or another signaling pathway such as the sonic hedgehog, Wnt cascades. Alternatively, a sufficient amount of cholesterol itself might be needed to support the structural demands of synaptogenesis.

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In the amyloid-cascade hypothesis, the deposition of B-amyloid protein in brain parenchyma is the pivotal event. B-amyloid deposition can be triggered by mutations in the gene encoding the APP or by binding to apoE4. B-amyloid deposition then leads to the formation of neuritic plaques, NFts and nerve cell death (Hardy, 1992).

A possible mechanism fro the spread of focal B-amyloid deposition in AD (Hardy, 1992)

1998

The relationships between BA and tau and between AD and FTDP-17 (front-temporal dementia). The link between BA42 overproduction and tau dysfunction is presently uncertain and represented by a ? mark. In addition, it is unclear whether tau dysfunction leads directly to cell death or if the formation of NFTs are a necessary intermediate (Hardy, 1998).

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The tau and tangle hypothesis. Tau binding to microtubules is disrupted by phosphorylation, directly by mutations that alter isoform expression. Decreased tau binding to microtubules might result in increased free tau which, under the appropriate conditions will self-aggregate to form insoluble paired helical filaments. ? Mark indicates the putative role of amyloid induced increased GSK-3 (glycogen synthethase kinase) activity that leads to increased tau phosphorylation (From Mudher and Lovestone, 2002).

?

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The wnt signalling hypothesis. Wnt transduces a signal through dvl and protein kinase C (PKC). Wnt and dvl increase secreted sAPP and inhibit glycogen synthase kinase 3 (GSK-3B) phosphorylation of tau. Both processes might be normal. Loss of wnt signal would result in decreased sAPP, increased tau phophorylation and both pathological hallmarks (plaques and tangles) of AD. JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase (Mudher and Lovestone, 2002)

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A: Anatomical organization of major perforant pathway innervation of hippocampus by axons originating in LII of the ipislat entorhinal cortex.

B: Disruption of perforant pathway causes changes in synaptic density in the outer two thirds of the dendrites of the dentate granule cells. Curves show approximate times for mRNA expressions for GFAP (glial fibrillary acidic protein), SGP2 (sulfated glycoprotein), vimentin, apolipoprotein (apoE), alfa1 tubulin, TGF-B (transforming growth factor) in the dentate gyrus (Finch and Day, 1994).

C: Multiple factors increase the neuroplasticity burden. Eventually the excessive neuroplasticity burden triggers plaque and NFT formation (Mesulam, 1999)

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• Cholinergic basal forebrain (BF) neurons (a) in normal physiological conditions and (b) as postulated in individuals with AD. In cholinergic neurons of the BF in individuals with AD, ChAT immunoreactivity, cell size and number, and NGF and TrkA levels are decreased. In the hippocampus of individuals with AD, ChAT levels and ACh-mediated signaling are reduced but NGF levels are increased or unchanged. In the hippocampus and BF of individuals with AD, APP expression and A aggregate levels are increased, whereas secreted (trophic) sAPPs are decreased. There are also degenerating terminals in the hippocampus. These altered levels indicate that NGF retrograde transport or NGF binding to trkA receptors, or both, are reduced in the individuals with AD, which results in inappropriate trophic support of the cholinergic system during degenerative disease

• A: amyloid ; ACh, acetylcholine; AD, Alzheimer's disease; APP, amyloid precursor protein; ChAT, choline acetyl transferase; DS, Down's syndrome; NGF, nerve growth factor; sAPP, soluble APP; TrkA, tyrosine receptor kinase A. (Isacson et al., 2002)

Potential Treatments for Alzheimer’s Disease 46

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Potential Treatments of AD (cont.)