Alzheimer’s disease sends the wrong signals – a perspective

RACHAEL L. NEVE

McLean Hospital, Belmont, MA 02478, USA

Keywords: Alzheimer’s disease, signaling, presenilin, amyloid precursor protein

Abbreviations: APP¼ amyloid precursor protein; FAD¼ familial Alzheimer’s disease; PI3K¼ phosphatidylinositol-3-kinase; GSK-3¼ glycogen synthase kinase 3; EGFR¼ epidermal growth factor receptor

AbstractFamilial Alzheimer’s disease mutations in presenilin and the amyloid precursor protein (APP) are thought to causeAlzheimer’s disease (AD) neurodegeneration by increasing production and aggregation of amyloid beta (Ab). However,presenilin has functions that are distinct from its role in the g-secretase complex, while APP has signaling functions thattranscend its role as the source of Ab. Three recent papers highlight the potential importance of presenilin and APP signalingin the etiology of AD.

Introduction

Presenilin is most commonly known as a component

of the g-secretase complex. It is in this capacity that

familial Alzheimer’s disease (FAD) mutations in

presenilin are thought to cause Alzheimer’s disease

(AD) neurodegeneration, the idea being that these

mutations cause gain-of-function changes in

g-secretase activity that result in increased accumula-

tion of amyloid beta1–42 (Ag1–42). However, pre-

senilin has signaling functions that are independent

of its role in g-secretase activity, raising the possibility

that loss of these functions may cause at least some of

the neurodegeneration and memory loss that occurs

in AD. One of the first hints that this may be the case

was the finding that presenilin knockout mice exhibit

impairments in hippocampal memory and long-term

potentiation which are followed by neurodegenera-

tion and tau hyperphosphorylation [1], suggesting

that normally presenilin possesses a neuronal survival

function that is lost in these animals.

FAD mutants of presenilin do not always

cause accumulation of Ab

Further buttressing the notion that there may be

more to the effects of FAD mutants of presenilin

than simple increases in g-secretase activity, it has

been shown that certain FAD presenilin mutations

actually decrease the g-secretase activity of this

molecule [2–4]. Moreover, wild-type presenilin,

consistent with the notion that it promotes neuronal

survival, protects against FAD amyloid precursor

protein (APP)-induced amyloid pathogenesis in

transgenic animals [5], whereas presenilin impaired

in g-secretase activity leads to exacerbated amyloid

pathology in FAD APP transgenic animals [6].

These findings suggest that FAD mutations of

presenilin may impair its function rather than cause

gain-of-function g-secretase activity. They also,

considered in the context of the Shen laboratory

work cited above, suggest that we should be looking

at other functions of presenilin besides its g-secretase

activity to find clues as to how FAD presenilin

mutants cause AD neuropathology.

FAD mutants of presenilin are impaired

in c-secretase-independent signaling

What might these other functions consist of? Work

from the Robakis laboratory [7] demonstrated that

presenilin inhibits apoptosis by promoting cadherin/

phosphatidylinositol-3-kinase (PI3K) association,

thereby activating PI3K/Akt cell survival signaling.

Presenilin AD mutations interfere with the

presenilin-dependent activation of the PI3K/Akt

signaling, and this interference results in increased

glycogen synthase kinase (GSK)-3 activity, overphos-

phorylation of tau at AD epitopes, and activation of

Correspondence: Dr. Rachael L. Neve, MRC223, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA. Tel: 617-855-2413. Fax: 617-855-3793.

E-mail: neve@helix.mgh.harvard.edu

Amyloid, March 2008; 15(1): 1–4

ISSN 1350-6129 print/ISSN 1744-2818 online � 2008 Informa UK Ltd.

DOI: 10.1080/13506120701814608

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apoptotic caspase-3 [7]. Consistent with this notion,

recent data from the Koo laboratory also show that

presenilin regulates the PI3K/Akt/GSK-3 pathway

[8]. Further supporting the idea that increased

GSK-3 activity may be important in the development

of AD neurodegeneration, Lucas et al. [9] and

Hernandez et al. [10] demonstrated that transgenic

mice overexpressing GSK-3 develop AD-like neuro-

pathology. In the first of the three papers highlighted

in this article, this same group has just shown that this

pathology, which includes tau hyperphosphorylation,

reactive astrocytosis, neuronal death, and spatial

learning deficits, can be reversed by decreasing

GSK-3 expression to normal levels [11]. They used

the elegant approach of conditionally overexpressing

GSK-3 in transgenic mice. Using the Tet-off system,

they dialed down the expression of the transgene by

administering a tetracycline analog to the mice for 6

weeks. The result was a full reversal of AD-like tau

hyperphosphorylation, restoration of microtubule

binding and stabilization ability of tau, reversal of

neuronal death and reactive gliosis, and rescue of

spatial memory impairment.

Such work highlights the importance of delineat-

ing the molecular mechanisms by which impairment

of the PI3K/Akt signaling function of presenilin

might lead to specific aspects of AD neurodegenera-

tion. The second of the three papers highlighted in

this perspective [12] describes such research. The

authors hypothesized previously, based on data from

their and other laboratories, that presenilins may be

involved in regulating certain signaling receptors

in a way that could modify the state of tau

phosphorylation and neuronal viability via the

PI3K/Akt pathway. In their current paper [12], they

present data in support of this hypothesis. They show

that the levels of epidermal growth factor receptor

(EGFR) are dramatically elevated in cells deficient in

presenilin, and in brains of presenilin conditional

knockout mice. Evidence is presented that the

elevation of EGFR in presenilin-deficient cells is

caused by impaired trafficking of EGFR from

endosomes to lysosomes. This phenotype was

rescued by expression of wild-type presenilin, but

not of FAD presenilin mutants, in the cells.

Importantly, several of these FAD presenilin mutants

retain their g-secretase activity. Further, g-secretase

inhibitors failed to mimic presenilin deficiency by

increasing EGFR levels, suggesting that the preseni-

lin g-secretase function is independent of the role of

presenilin in EGFR signaling.

FAD mutants of APP also send mixed signals

These two recent papers build an increasingly

strong case for the notion that impairment of

presenilin signaling, rather than gain-of-function

of its g-secretase cleavage activity, may be critical

for the development of AD neurodegeneration

(Figure 1). Does this mean that we should be

looking at alternative functions for the amyloid

precursor protein (APP) as well, beyond its role as

the source of the beta-amyloid peptides that

accumulate in the brains of patients with AD?

Probably. A multitude of cytosolic proteins that

interact with the APP cytodomain have been

Figure 1. Presenilin 1 possesses g-secretase-independent signaling functions. In a g-secretase-independent pathway, wild-type presenilin 1

promotes cadherin-mediated activation of the PI3K-Akt pathway, thereby suppressing apoptosis and GSK-3 activity and preventing GSK-3-

mediated overphosphorylation of tau. FAD mutants of presenilin 1 appear to interfere with this function of presenilin 1, leading to

suppression of PI3K/Akt signaling, overactivation of GSK-3, hyperphosphorylation of tau and neuronal death [7–9,12]. Presenilin 1 also

participates in g-secretase-dependent signaling pathways that regulate transcription [reviewed in ref. 20].

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described [reviewed in ref. 13] suggesting that APP

has versatile signaling roles.

All but one of the binding proteins for the APP

cytodomain interact with APP within the last 31

amino acids of this domain (Figure 2). Why is this

significant? For one thing, C31 can be generated

from APP by caspase cleavage [14,15]. Furthermore,

this cleavage has functional significance: expression

of C31 alone has been shown to cause neuronal cell

cycle entry and apoptosis [15–17]. Most recently, in

the third paper highlighted in this commentary,

inhibition of C31-producing caspase cleavage of APP

prevented the development of AD-like pathology and

behavior caused by the Indiana and Swedish FAD

mutations of APP [18]. The authors of this paper

introduced the D664A mutation (which prevents

the generation of C31) into the background of a

human APP minigene carrying the K670N/M671L

(Swedish) and V717F (Indiana) mutations. Both the

original FAD mutant minigene (PDAPP) and also

the D664A version of it [PDAPP(D664A)] were

expressed in transgenic mice under the control of the

PDGF B-chain promoter.

The D664A mutation did not alter the net

in vivo production of Ab40 and Ab42 in the brains

of the mice, nor did it affect the extent of amyloid

plaque deposition in PDAPP(D664A) mice com-

pared with PDAPP mice. However, the D664A

mutation did have an effect on neurodegeneration

and on behavior. While the PDAPP mice displayed

decreased hippocampal presynaptic density num-

ber, increased GFAP immunoreactivity in the

hippocampus, loss of dentate gyrus volume, and

impaired spatial learning, relative to controls, the

PDAPP(D664A) mice were indistinguishable from

controls in these parameters. A subsequent study

[19] showed that PDAPP mice have impaired

synaptic transmission, synaptic plasticity, and

learning; and that the PDAPP(D664A) mutation

rescued these abnormalities despite elevated levels

of Ab42 and plaque accumulation in these trans-

genic mice.

From these data, it can be inferred that if C31

cannot be generated from APP carrying FAD

mutations, multiple aspects of neuropathology, im-

paired learning, and impaired deficits in synaptic

transmission that are normally caused by these

mutations do not occur. What are the implications

of these findings? First of all, note that Asp664

selectively rescues the neurodegeneration and the

learning abnormalities of the PDAPP mice without

decreasing the production of Ab40 or Ab42. Thus, the

rescue is independent of the production of Ab.

Figure 2. All but one of the APP cytodomain-binding proteins that have been identified bind to the C-terminal 31 amino acids of APP

[reviewed in ref. 13]. These include the p21-activated kinase 3 (PAK3) [15], APP-binding protein 1 (APP-BP1) [16], the heterotrimeric G

protein Go [21], and multiple intracellular adaptor proteins [reviewed in ref. 22].

Figure 3. C31, when released from FAD APP by caspase cleavage,

may abnormally activate or disrupt signaling pathways mediated by

APP. In the scenario shown, both APP-BP1 and a complex that

includes Go and PAK3 bind to the C-terminus of APP, not

necessarily simultaneously. Also interacting with the C-terminus

of APP but not shown are a number of intracellular adaptor

proteins [reviewed in ref. 20]. Caspase cleavage of FAD APP,

which occurs preferentially on the b-secretase cleavage product,

C99 [14], releases C31, which has been shown to cause abnormal

neuronal DNA synthesis and apoptosis mediated by PAK3 and

APP-BP1 [15,16].

Faulty signaling in Alzheimer’s disease 3

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Secondly, the C31 region of APP encompasses the

binding sites for nearly all of the signaling proteins

that have been shown to bind to the intracellular

domain of APP. The data suggest a scenario in which

C31, when removed from APP, may abnormally

activate or disrupt signaling pathways mediated by

APP (Figure 3). Such a scenario is supported by the

findings that caspase-cleaved APP and activated

caspases are present in the brains of AD patients

but not in control brains [15], and that expression of

C31 alone causes apoptosis [15,16].

Concluding remarks

The trio of papers discussed in this commentary,

taken together with the body of work preceding

them, make the case that not only Ab production,

but also presenilin and/or APP signaling is likely to

be important in the etiology of AD. Studies that

delineate the normal signaling pathways mediated by

presenilin and APP are to be encouraged, for they are

certain to help us understand how signal transduc-

tion by these proteins goes awry in AD.

Acknowledgements

I thank Nikolaos Robakis for numerous helpful

discussions. I also thank Lia Baki for the Figure 1

artwork and Donna McPhie for designing Figures 2

and 3.

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