Alzheimer’s Disease

Bi156 2/27/12

Paul Patterson

Alzheimer’s disease

• The primary feature of AD is a profound dementia that robs people of

memory, a key feature of social interaction, and the essence of personal

identity.

• Since AD does not shorten lifespan significantly, the typical patient can live

for years without knowing who they are or recognizing their relatives or

friends, despite being healthy in other respects.

• There are 450,000 new cases of AD each year in the US currently, and the

prevalence is expected to double in the next 20 years, at which time ~0.5%

of the total population will have the disease - if there is no effective treatment

developed.

• In 2010, the global economic impact of dementias was $604B, which dwarfs

the costs of cancer or heart disease. This cost is predicted to increase 85%

by 2030.

• It is estimated that a treatment that would delay AD onset by even 1 year

would result in an annual savings of $10B in the US alone. This is because it

is a disease of the elderly, and many people would die before getting the

disease.

Alzheimer’s disease - II

• AD is preceded by a pre-clinical period of many years, during which memory

difficulties exceed those of normal aging.

• A state of dementia is confirmed when memory loss undermines the

capacity for independent living.

• Normal aging involves a decline in memory capacity; on a delayed recall

test, average performance for a 30 yr-old is 31, while a normal 70 yr-old is

15. A demented person may score 0.

• Currently approved drugs for AD are of very limited benefit.

• The cause of AD is unknown, but a small fraction is due to mutation.

• The cause of memory loss is likely the progressive death of neurons in (or

projecting to) the limbic system - and/or the loss of their synapses.

• Prominent among these is the cholinergic projection from the basal forebrain

to the hippocampus and cortex.

Neurons vulnerable in AD

Widespread cortical thinning in AD and mild

cognitive impairment

Cortical thickness was compared point by point across the entire cortical mantle between NC and MCI patients and between NC and AD patients. Sex and age

were used as covariates. The results are shown as p value maps, thresholded at FDR 0.05. As can be seen, MCI patients have thinner cortex than NC in large

cortical areas, including medial, lateral, and inferior temporal cortices, medial parietal cortex, and widespread areas in frontal cortex. The differences between NC

and AD patients are even larger, covering the major part of the cortical surface, except the area around the central sulcus. NC, normal control; MCI, mild cognitive

impairment; AD, Alzheimer’s disease Fjell et al., 2010

AD pathology

• The diagnostic features of AD pathology are -amyloid plaques and

neurofibrillary tangles (NFTs).

Plaques and neurofibrillary tangles

Haas & Selkoe, 2007

AD

PD

AD

Prion

HD

AD pathology - NFTs

• The NFTs are insoluble, intracellular polymers of hyper-phosphorylated

tau, a cytoskeletal protein that, in its normally phosphorylated form,

stabilizes microtubules in axons.

• Both plaques (amyloid) and tangles are indicative of AD and dementia;

which is more important? (Tauists versus Baptists)

• The NFTs are thought to interfere with cytoskeletal function, leading to

synapse loss and neuronal death. Thus, hyper-phosphorylation of tau

could be a proximate cause of AD.

• In fact, NFTs first form in paralimbic and limbic structures, which are

important for learning and memory.

• There is a good correlation between dementia and the frequency of

NFTs at autopsy.

Neurofibrillary

tangles & tau

Querfurth & LaFerla, 2010

Four repeat sequences (R1-R4) make up the

microtubule-binding domain (MBD) of tau. Normal

phosphorylation of tau occurs on serine

(S; inset, above horizontal bar) and threonine (T;

inset, below horizontal bar) residues, numbered

according to their position in the full tau sequence.

When followed by proline (P), these amino acids are

phosphorylated by glycogen synthase kinase 3 (GSK-

3β), cyclin-dependent kinase (cdk5) and its activator

subunit p25, or mitogen-activated protein kinase

(MAPK). Nonproline-directed kinases — Akt, Fyn,

protein kinase A (PKA), calcium–calmodulin protein

kinase 2 (CaMKII), and microtubule affinity-regulating

kinase (MARK) — are also shown. KXGS (denoting

lysine, an unknown or other amino acid, glycine, and

serine) is a target motif. Hyper-phosphorylated sites

specific to paired helical filament tau in Alzheimer’s

disease tend to flank the MBD. Tau binding promotes

microtubule assembly and stability. Excessive kinase,

reduced phosphatase activities, or both cause

hyperphosphorylated tau to detach and self-

aggregate and microtubules

to stabilize.

NFT - II

• There is no known genetic link between AD and NFTs, but there are

several neurodegenerative diseases with NFT accumulation that involve

dementia - in the absence of plaques.

• Frontal-temporal dementia with parkinsonism (FTDP) can be caused by

mutations in tau.

• FTDP has symptoms in common with AD, except for frontal lobe signs

(disinhibition, apathy).

• FTDP pathology includes atrophy of frontal and temporal lobes, with

neuronal loss and gliosis. NFTs can be similar or different from those in

AD.

• Importance: (i) tau dysfunction can lead to neurodegeneration; (ii)

amyloid deposition is not an inevitable consequence of tau dysfunction.

• Other tau mutations can lead to different neurodegenerative diseases

such as Pick’s and progressive supranuclear palsy. But the absence of

tau mutations leading to AD is a key puzzle.

The amyloid (A) cascade hypothesis

Haas & Selkoe, 2007

Plaques and APP processing

• Plaques containing amyloid protein accumulate in the extracellular

space during normal aging, but the frequency is much higher in AD.

• Plaques contain insoluble fibrils of the amyloid (A) fragment of the

larger amyloid precursor protein (APP).

• APP is a transmembrane protein that is processed by 3 proteases: the

-, -, and - secretases.

• The latter two enzymes yield products that contain A

Synthesis and processing of the precursors of the A amyloid peptide. The amyloid precursor proteins APP-751 and APP-

770 contain a domain that is homologous with the serine protease inhibitors (KPI). APP-695 lacks this domain. Top: The

extracellular, transmembrane, and cytoplasmic domains of A amyloid. Bottom: The detail of the peptide shows the sites of -,

-, and -secretase cleavages and the nature and position of several APP mutations linked to familial Alzheimer disease. The

endopeptidase -secretase cleaves within the A region, resulting in the secretion of the extracellular domain of APP; hence, the

cleavage does not produce the A peptide. In contrast, the -secretase and -secretase cleavages do result in production of the

peptide.

APP processing

pathways

In Panel A, cleavage by α-secretase interior to

the β-amyloid peptide (Aβ) sequence initiates

nonamyloidogenic processing. A large amyloid

precursor protein (sAPPα) ectodomain is

released, leaving behind an 83-residue carboxy-

terminal fragment. C83 is then digested by

γ-secretase, liberating extracellular p3 and the

amyloid intracellular domain (AICD).

Amyloidogenic processing is initiated by β-

secretase beta-site amyloid precursor protein–

cleaving enzyme 1 (BACE-1), releasing a

shortened sAPPα. The retained C99 is also a γ-

secretase substrate, generating Aβ and AICD. γ-

Secretase cleavage occurs within the cell

membrane in a unique process termed “regulated

intramembranous proteolysis.” sAPPα and

sAPPβ are secreted APP fragments after α-

secretase and β-secretase cleavages,

respectively. AICD is a short tail (approximately

50 amino acids) that is released into the

cytoplasm after progressive ε-to-γ cleavages by

γ-secretase. AICD is targeted to the nucleus,

signaling transcription activation. Lipid rafts are

tightly packed membrane micro-environments

enriched in sphingomylelin, cholesterol, and

glycophosphatidylinositol (GPI)–anchored

proteins. Soluble Aβ is prone to aggregation. In

Panel B, left inset, protofibrils (upper) and annular

or porelike profiles (lower) are intermediate

aggregates. In the right inset, self-association of 2

to 14 Aβ monomers into oligomers is dependent

on concentration (left immunoblot). In the right

immunoblot, oligomerization is promoted by

oxidizing conditions (lane 2) and divalent metal

conditions (lane 3). Querfurth & LaFerla, 2010

Plaques and APP processing II

• The long form of A (A42) is insoluble, found in plaques, and some

investigators find that it is neurotoxic in culture.

• Thus, one theory is that abnormal processing caused by mutations in

APP yields A42, which directly causes neuronal death.

• The -secretase (BACE) is key target for drug development, especially

since the BACE KO mouse is apparently normal.

BACE1 KO blocks cerebral A accumulation

Ohno et al., ‘04

BACE KO rescues memory deficits in APP mouse

A) Social recognition memory assayed with 3hr intertrial delay. Only the KO (Tg) does not show a reduction in spontaneous investigation of a familiar

mouse. (B) Spontaneous alternation Y maze performance in spatial memory shows Tg does poorly.(C) Total arm entries reflecting exploratory behavior.

Ohno et al., ‘04

APP mutations and AD

There is an impressive body of evidence linking APP mutations with AD:

• Mutations in APP are sufficient to cause early onset AD.

• All APP mutations that cause AD also lead to greater production of the long form of A

• Down’s syndrome (trisomy 21) leads to an extremely early onset of AD pathology and an over-production of APP and A

• Acan kill neurons and cause hyper-phosphorylation of tau.

• Mutations in presenilin1 or 2 (PS1, 2) that cause AD also lead to greater production of the long form of A

• The E4 allele of apolipoprotein E (APOE), a major risk factor for AD, promotes precipitation of A into plaques.

• Over-expression of AD-causing mutants of APP in some transgenic mouse lines causes amyloid plaque deposition, tau phosphorylation, and some damage to synapses and neurons, leading to deficits in learning and memory.

Plaques form in

APP Tg mice

Mutant human APP expression

was driven in neurons by the Thy-

1 promoter (APP23 mouse line).

(A,C,E) 18 mo-old. (B,D,F) 24 mo-

old. (A,B) In situ hybridization for

APP. (C,D) Congo red staining for

plaques. (E,F) Staining for A

Sturchler-Pierrat et al., ‘97

Tau phosphorylation and NFTs in APP23 mice

APP Tg mice show water maze learning deficit

(a-c) Diffuse amyloid deposition in APP Tg mice of different ages. (d) Plot of plaque burden in the hippocampus as

a function of age. (e) Two measures of performance in learning a series of spatial locations in the water maze as a

function of plaque burden. (f) Scatter plot of learning scores (number of platform locations learned to criterion in

10d) in the subset of middle-age and old animals.

Janus et al., ‘02

Learning deficit in APP Tg mice

Janus et al., ‘02

Presenilins

• PS1 & 2 are membrane proteins found primarily in the ER and Golgi.

• Autosomal dominant mutations in either of these genes can cause early onset AD.

• Cultured cells and Tg mice expressing PS1 or PS2 mutations have higher A42/A4 ratios, suggesting a role in APP processing.

• Cells lacking PS1 produce very low levels of both peptides due to decreased cleavage at the -secretase site.

• PS is found in protein complexes with -secretase activity, as is nicastrin, a protein required for -secretase processing of A

• PS = -secretase ?

PS1 mutation accelerates plaque formation

and astrocyte activation in APP Tg mice

Siman et al., ‘00

Apolipoprotein E and AD

• APOE is a strong risk factor for AD: mutations in the APOE4 allele

decrease the age of AD onset, while presence of the APOE2 allele is

somewhat protective.

• Expression of the APOE4 allele leads to enhanced accumulation of A

in the brains of carriers as well as in Tg mice expressing the human

APOE4 allele and mutant APP.

APOE is important for amyloid deposition

in APP Tg mice

Bales et al., ‘99

Apolipoprotein E and cholesterol II

• APOE has a role in cholesterol transport and lipid metabolism - what

has this to do with AD?

• High plasma cholesterol is correlated with increased A deposition, and

statins given to lower cholesterol decrease A levels in the human

brain.

Reducing cholesterol

lowers A(reversibly)

Fassbender et al., ‘01

Apolipoprotein E and cholesterol III

• Cholesterol also increases A production and stabilizes the peptide in the

brains of APP mice.

• Thus, it is possible that APOE4 confers risk for AD via a mechanism that

is shared with its effect on cardiovascular disease: Increasing the risk for

hypercholesterolemia.

• Importantly, statin use lowers the incidence of AD (79% decrease in risk).

• Statins also have anti-inflammatory effects.

• Cholesterol in the membrane affects APP cleavage to yield A

Can mutant APP kill neurons directly?

A can form pores/channels in membranes

synuclein mutant

synuclein mutant

APP mutant

Mutant AD and PD proteins can form annular protofibrils that resemble a class of pore-forming

bacterial toxins:

These proteins (as well as mutant huntingtin and prion proteins) can facilitate ion fluxes when

inserted into membranes in vitro.

Lashuel et al.,2000

Secreted A oligomers block LTP

Haas & Selkoe, 2007

Issues regarding Aplaques and AD

Hypothesis: Over-production of A(or failure to clear it) leads to plaques, tau dysfunction and neuronal death.

• In contrast to NFTs, plaque frequency and distribution does not correlate with dementia: initial deposition tends not to be in limbic areas, and extensive plaque deposition has been found in non-demented individuals.

• There is no correlation between local plaque density and NFTs.

• NFTs tend to appear before plaques.

• In many strains of APP Tg mice, huge plaque loads do not lead to neuronal death or NFT formation.

• The behavioral and electrophysiological abnormalities in Amutant mice can precede plaque formation.

• Thus, plaques may be the pathological endpoint (tombstones) rather than a step on the way to neuronal death.

• Perhaps it is the concentration of soluble oligomers of Athat is the key, and this is not normally visualized in autopsy specimens. However, it is thought that plaques are formed by high local concentration of A

Potential therapies: APP immunization

• In an effort to block plaque formation, Tg mice over-expressing a

human APP gene that contains an AD-causing mutation were

immunized with A (active immunization) or given anti-A antibodies

(passive immunization).

• Plaque formation was blocked, as was astrocyte activation.

• Immunization of older mice markedly reduced the extent and

progression of pathology, and even reversed it.

A immunization blocks rise in amyloid burden

in APP Tg mice

Selkoe & Schenk, ‘03

A immunization reduces plaques

Shenk et al., ‘99

12 mo 18 mo, untreated 18 mo, immunized

APP immunization II

• Imaging in live APP mice showed that topical application of A

antibodies to the brain clears A deposits in 3 days.

• A42 levels were 80% reduced while total APP levels were unaltered,

suggesting APP processing is altered or A42 is selectively eliminated.

• A antibodies can also clear tau pathology in AD mice.

• Immunization prevents memory loss in these APP mice, and even

reverses learning deficits in older mice!

A immunization improves learning in Tg mice

Radial arm water maze performance was tested in

vaccinated and non-vaccinated Wt and transgenic mice. (a)

Non-Tg mice (circles, solid lines), Tg mice vaccinated with

KLH (squares, dashed lines), and Tg mice vaccinated with A

(triangles, dotted lines) were tested in maze at 11.5 mo, after 5

innoculations. All groups learned (trial 4) and remembered

(trial 5) the platform location at this time point. In the same mice

at 15.5 months of age (9 innoculations)(b), the Tg mice

vaccinated with A continued to show learning and memory of

platform location, while the Tg mice vaccinated with KLH failed

to show this on either trials 4 or 5. This benefit of A vaccination

was found in both the APP-only and APP+PS1 Tg mice (c), with

significantly fewer errors on trial 5 in the A-vaccinated groups

(solid bars) than in the KLH-vaccinated group (open bars).

Included for comparison is the trial 5 performance of another

Group (hatched bars) of untreated 15-16 mo-old Tg mice that

were tested separately and reported on fully elsewhere.

Morgan et al., 2000

11.5 mo

15.5 mo

KLH

Imm’d

A Imm’d

Will APP immunization be a miracle cure?

• Some years ago, a biotech company, Elan, began clinical trials

immunizing AD patients with human A42

• Worries: Would the patients’ antibodies attack the A in their blood

vessels, kidneys, etc; will a cellular immune response cause an

autoimmune response like that in MS?

• No such side reactions were observed in the APP mice, but they

expressed human A42 and were immunized with that protein.

• However, a small fraction of the patients in the French trial came down

with neuro-immune problems (encephalitis) and the trial was halted.

• Analysis of the patients in the trial did, however, show that treatment

was effective in slowing cognitive decline.

A Abs slow cognitive decline in some AD patients

Hock et al., ‘03

A immunization decreases tau phosphorylation

and NF-tangles

Serrano-Pozo et al., ‘10

(A) Hippocampal density of PHF1-positive neurons is significantly decreased in the immunized Alzheimer’s disease patients compared to

the patients with non-immunized Alzheimer’s disease, despite both groups being matched for Braak stage. (B, C) No significant difference

is observed in the densities of Alz50-positive neurons and thioflavin-S positive neurofibrillary tangles (NFT) between both Alzheimer’s

disease groups. Pairwise comparisons in A–C were done with a two-tailed t-test and bars represent meanSEM (*P50.05, **P50.01,

#P50.0001). (D) Correlations between densities of PHF1-positive neurons and Alz50-positive neurons in both Alzheimer’s disease groups

reveal a predominance of the late-stage phospho-tau species (PHF1) over the early-stage misfolded tau species (Alz50) in the non-

immunized group. By contrast, neither of both tau epitopes is predominant in the Braak-matched immunized Alzheimer’s disease group.

Black circles represent each of non-immunized patients and grey squares represent immunized patients. Correlations were done with

Pearson’s test and dotted lines indicate the 95% confidence interval. For clarity purposes, non-demented controls are not represented.

A and

mitochondria

Querfurth & LaFerla, 2010

A β-amyloid peptide (Aβ)–centric scheme depicts

production of reactive oxygen species (ROS) and

reactive nitrogen species (RNS). Their peroxidative

attack on cell and organelle membrane lipids yields

the mitochondrial toxins hydroxynonenal (HNE)

and malondialdehyde. Oxidative damage to

membrane-bound, ion-specific ATPases and

stimulation of calcium (Ca2+) entry mechanisms —

for example, glutamate NMDAr, membrane-attack

complex (MAC) of complement, and ion-selective

amyloid pore formation — cause cytosolic and

mitochondrial Ca2+ overload. Cellular Aβ directly

attacks electron transport complex IV (cytochrome

c oxidase) and key Krebs-cycle enzymes (α-

ketoglutarate and pyruvate dehydrogenase) and

damages mitochondrial DNA (mtDNA), leading to

fragmentation. Lipid peroxidation products also

promote tau phosphorylation and aggregation,

which in turn inhibit complex I. Exaggerated

amounts of ROS and RNS are generated at

complexes I and III. As the mitochondrial

membrane potential (MPP) collapses and

permeability-transition pores (ψm) open, caspases

are activated. Aβ also induces the stress-activated

protein kinases p38 and c-jun N-terminal kinase (

JNK), as well as p53, which are further linked with

apoptosis. Substrate deficiencies, notably NADH

and glucose, combine with electron transport

uncoupling to further diminish ATP production.

Alcohol dehydrogenase was recently identified as

the mitochondrial-binding target for Aβ.

Endoplasmic reticulum contributions are shown.

GLUT1, 4 denotes glucose transporter 1,4.

Therapeutic approaches targeting Aand tau

currently in clinical testing

Golde et al., 2010

Prion-like spread of abnormal tau?

Liu et al., 2012

Monosynaptic and trans-synaptic cortico-hippocampal and cortico-cortico connections are illustrated. Solid lines indicate projections

radiating out from the entorhinal cortex (EC), dotted lines indicate projections to the EC. Monosynaptically connected regions are

connected across one synapse. Trans-synaptic regions are separated by more than one synapse.

The earliest stages of AD show accumulation of abnormal tau in the EC, while later stages show accumulation in the

hippocampus followed by neocortical areas.

Progressive spread of tau pathology in vivo

Liu et al., 2012

A Tg mouse model was generated with restricted

expression of human tau predominantly in the EC. Fig.

2A shows tau immunolabeled with the human tau specific,

conformational antibody MC1 in a young (10-11 mo) NT

mouse at low power, and higher power (Figs. 2D, G). Fig. 2B

shows MC1 immunolabeling in an old (22 mo) NT mouse at

low power, and higher power (Figs. 2E, H). Fig. 2F shows

high power image of cells immunolabeled with MC1 within

the MEC. Old NT mice show extensive accumulation of

human tau in cell bodies in the EC and subiculum (Fig. 2H),

and in synaptically connected areas in the hippocampus and

neocortex (Fig. 2E). Fig. 2I shows accumulation of human

tau in neurons of the perirhinal cortex and into the parietal

region in the old NT mouse. Note the lack of neurite staining

in the perirhinal cortex compared to the LEC. Fig. 2C shows

lack of immunolabeling with the human specific antibody in

an old, littermate control mouse (single transgenic tau

responder mouse, no tTA) except for the non-specific

staining of the fornix that was seen with all antibodies.

MEC = medial entorinal cortex, LEC = lateral entorhinal

cortex, Pe = perirhinal cortex, Par = parietal cortex, DG =

dentate gyrus, CA1, CA3 = CA fields of hippocampus, Su =

subiculum, Prp-PaS = pre-parasubiculum, pp = perforant

pathway endzone.

Transynaptic spread of tau pathology in vivo

Liu et al., 2012

Young NT mice (Fig. 4A) show accumulation of human tau immunolabeled with CP27 predominately in the endzones of the perforant

pathway that terminate in the middle third of the molecular layer of the DG (area 3). Terminals from neurons in the LEC terminating in the

outer third of the molecular layer are shown in area 4. Human tau was also seen in cells in the hilus (area 1). Granule cell layers of the DG

(area 2) did not accumulate human tau at this age. Old NT mice (Fig. 4B) show accumulation of human tau in cell bodies in the granule cells

of the DG (area 2). Increased accumulation of human tau is seen in layers 1, 2 and 4 but the perforant pathway endzone in layer 3 was

significantly depleted of tau.

Inflammation and AD

• AD brains display activated microglia and astrocytes surrounding the

plaques. Microglia are the principle immune cells of the brain,

responding to various stimuli by expressing MHC II, complement

receptors and Ig receptors, and secreting pro-inflammatory cytokines.

• Such cytokines (IL-1 and -6, LIF, TNF) are found at high levels

around plaques in AD.

• Is this inflammation part of the cause of memory loss (synaptic deficits),

or is it involved in mopping up the damage?

• Epidemiological studies show that people treated for extended periods

(>6 months) with non-steroidal anti-inflammatory drugs (NSAIDs) for

various problems such as arthritis, have a delayed onset of AD. This is

also true in twin studies where one twin was taking NSAIDs.

• Non-steroidal anti-inflammatory drugs (NSAIDs) reduce A deposition

and learning deficits in APP mice.

Inflammation &A

β-amyloid peptide (Aβ) is formed within

intracellular compartments (the endoplasmic

reticulum, Golgi apparatus, and endosomes) or

it can enter multiple cell types through the low-

density lipoprotein receptor–related protein. The

ubiquitous apolipoprotein E (APOE) and α2-

macroglobulins (α2M) are chaperones in this

process and in the genesis of extracellular

plaques. Microglia directly engulf Aβ through

phagocytosis. Astrocytes also participate in Aβ

clearance through receptor-mediated

internalization and facilitation of its transfer out

of the central nervous system and into the

circulation. Microglia and astrocytes are

recruited and stimulated in Alzheimer’s disease

to release proinflammatory cytokines and acute-

phase reactants. Receptors for advanced

glycation end products (RAGE) molecules

transduce extracellular Aβ toxic and

inflammatory effects and mediate influx of

vascular Aβ. The inflammatory milieu provokes

neuritic changes and breakdown of the vascular

blood–brain barrier. In addition to cell-mediated

reactions, Aβ clearance occurs through

enzymatic proteolysis, mainly through neprilysin

(Nep) and insulin-degrading enzyme (IDE). Aβ

oligomers block proteasome function, facilitating

the buildup of intracellular tau and accumulation

of Aβ into “aggresomes.” APP denotes amyloid

precursor protein, MMP matrix

metalloproteinase, MOTC microtubule

organizing center, MVB multivesicular body.

Querfurth & LaFerla, 2010

Cell infiltration in neurodegenerative disease

Lucin & Wyss-Coray, 2009

Activated microglia

are associated with

plaques

(A) MAC-1 stained microglia

associated with amyloid deposits

in cortex and hippocampus of

App23 Tg mice. (B) Higher mag

of A. (C) Stained non-Tg brain.

(D) F4/80 microglial staining of

APP23 brain. (E) F4/80 staining

of non-Tg brain.

Non-steroidal anti-inflammatory drug use delays AD

Breitner et al., ‘95

NSAID lowers plaques in APP Tg mouse

Frontal cortex

Hippocampus

Control NSAID-treated

APP-PS1 double transgenic mice were given the NSAID NCX-2216 from 7 to 12 months of age.

NSAID activates microglia in APP Tg mouse Control NSAID-treated

MHC-II staining

CD-11 staining

Double transgenic AD mice given NCX-2216 NSAID for 14 days surprisingly showed microglial

activation rather than suppression.

LPS-induced inflammation increases plaques

in APP Tg mice

Qiao et al.,’01

Systemic inflammatory episode exacerbates

cognitive decline in AD

Holmes et al.,2009

ADAS-COG Alzheimer’s Disease Assessment Scale–Cognitive subscale; SIE systemic inflammatory events

(infection, trauma, myocardial infarction)

Inflammation and AD III

• A clinical trial of Celebrex (COX2 inhibitor) was unable to demonstrate a

benefit in established AD.

NSAID targets depend on stage of disease

and type of drug used

Sastre & Gentleman,’10

Divergent views on inflammation trials

• Colin Masters: “These results are not surprising, as we know that AD is

not caused by inflammatory processes. Indeed, the exact opposite seems

to be true - the microglia in AD brains are probably beneficial in the brain’s

response to the deposition of neurotoxic A…it is not a good idea to try to

impair the natural healing response of the brain.”

• Tony Wyss-Coray: “Many arguments can be made as to why this first

primary prevention trial testing 2 different NSAIDs, similar to previous

treatment trials, showed no benefit: the choice of NSAIDs, the duration of

treatment , or the advanced age or presymptomatic neurodegeneration in

the subjects. But maybe we should look elsewhere. A fundamental

difference between the epidemiological trials and the drug trial is that

NSAID prescription in the former is probably triggered by an inflammatory

disease, whereas the current prevention trial select subjects without

“confounding” chronic inflammatory diseases. Thus, is it possible that

systemic inflammatory conditions, alone or in combination with NSAIDs,

protect against AD?

Modified -amyloid hypothesis

Neurotrophic factor therapy

• Since loss of cholinergic neurons is a cardinal symptom of AD, and NGF

is neurotrophic for these neurons, NGF was tested in AD model

mice and found to be effective in blocking memory loss.

• NGF is now in a Phase II clinical trial of AD - implanting autologous

fibroblasts secreting NGF into the forebrain.

Implanted cells secreting NGF increase brain

metabolism over 6-8 months

Tuszynski et al., 2005

4 subjects treated with NGF

PET imaging for FDG

Implanted cells secreting NGF increase outgrowth

from cholinergic neurons in 5 weeks

Tuszynski et al., 2005

Cholinergic fibers in graft

Implanted cells secreting NGF

slow the rate of decline in mental function

Tuszynski et al., 2005

References

Background

* Selkoe DJ (2011) Resolving controversies on the path to Alzheimer’s therapeutics. Nature Med 17:1060-5.

* Kandel, ER, Schwartz, JH and Jessell, TM (2000) “Principles of Neuroscience”, 4th edition, McGraw Hill, Chap. 58.

Student papers

* Craft S, Baker LD, Montine TJ, Minoshima S et al. (2012) Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment. Arch Neurol 69:29-38.

* Eisele YS, Obermuller U, Heilbronner G, Baumann F, Kaeser SA, Wolburg H, Walker LC, Stuafenbiel M, Heikenwalder M, Jucker M (2010) Peripherally applied A-containing inoculates induce cerebral -amyloidosis. Science 330:980-2.