Cell membranes are dynamic and complex structures, and their composition and structure are major determinants of pathology. It is now commonly accepted that the membranes' physical properties, such as fluidity and thickness, are determining factors for permeability, partitioning of drug molecules, and protein aggregation. Membrane-interacting molecules can in some instances be expected to have a greater therapeutic potential than traditional therapies targeting receptors or enzymes. Alzheimer's disease is an example where traditional approaches thus far have been proven unsuccessful. With bacteria becoming resistant to more and more antibiotics, potential membrane based antibiotics provide an alternative route with great potential. Here, we provide a perspective on the basic mechanisms how physical membrane properties can affect diseases and the therapeutic potential of changing membrane lipid composition and properties to target those diseases. Neurodegenerative diseases, such as Alzheimer's disease, and infectious diseases, are prime examples among many others where the so-called Membrane-Lipid Therapy shows great potential for the development of new drugs and new therapies.

1.
S.
Singer
and
G. L.
Nicolson
, “
The fluid mosaic model of the structure of cell membranes
,”
Day Good Membr. Viruses Immunopathol.
175
,
7
47
(
1972
).
2.
K.
Simons
and
E.
Ikonen
, “
Functional rafts in cell membranes
,”
Nature
387
,
569
572
(
1997
).
3.
L.
Toppozini
,
S.
Meinhardt
,
C. L.
Armstrong
,
Z.
Yamani
,
N.
Kučerka
,
F.
Schmid
, and
M. C.
Rheinstädter
, “
Structure of cholesterol in lipid rafts
,”
Phys. Rev. Lett.
113
,
228101
(
2014
).
4.
M. C.
Rheinstädter
and
O. G.
Mouritsen
, “
Small-scale structure in fluid cholesterol–lipid bilayers
,”
Curr. Opin. Colloid Interface Sci.
18
,
440
447
(
2013
).
5.
J. D.
Nickels
,
M. D.
Smith
,
R. J.
Alsop
,
S.
Himbert
,
A.
Yahya
,
D.
Cordner
,
P.
Zolnierczuk
,
C. B.
Stanley
,
J.
Katsaras
,
X.
Cheng
 et al, “
Lipid rafts: Buffers of cell membrane physical properties
,”
J. Phys. Chem. B
123
,
2050
2056
(
2019
).
6.
W. K.
Subczynski
and
A.
Wisniewska
, “
Physical properties of lipid bilayer membranes: Relevance to membrane biological functions
,”
Acta Biochim. Pol.
47
,
613
626
(
2000
).
7.
P. V.
Escribá
,
J. M.
González-Ros
,
F. M.
Goñi
,
P. K.
Kinnunen
,
L.
Vigh
,
L.
Sánchez-Magraner
,
A. M.
Fernández
,
X.
Busquets
,
I.
Horváth
, and
G.
Barceló-Coblijn
, “
Membranes: A meeting point for lipids, proteins and therapies
,”
J. Cell. Mol. Med.
12
,
829
875
(
2008
).
8.
R.
Phillips
,
T.
Ursell
,
P.
Wiggins
, and
P.
Sens
, “
Emerging roles for lipids in shaping membrane-protein function
,”
Nature
459
,
379
385
(
2009
).
9.
V.
Martín
,
N.
Fabelo
,
G.
Santpere
,
B.
Puig
,
R.
Marín
,
I.
Ferrer
, and
M.
Díaz
, “
Lipid alterations in lipid rafts from Alzheimer's disease human brain cortex
,”
J. Alzheimer's Dis.
19
,
489
502
(
2010
).
10.
S.
Sameni
,
L.
Malacrida
,
Z.
Tan
, and
M. A.
Digman
, “
Alteration in fluidity of cell plasma membrane in Huntington disease revealed by spectral phasor analysis
,”
Sci. Rep.
8
,
734
(
2018
).
11.
S. S.
Antollini
and
C.
Fabiani
, “
Alzheimer's disease as a membrane disorder: Spatial cross-talk among beta-amyloid peptides, nicotinic acetylcholine receptors and lipid rafts
,”
Front. Cell. Neurosci.
13
,
309
(
2019
).
12.
K. F.
Herold
,
O. S.
Andersen
, and
H. C.
Hemmings
, “
Divergent effects of anesthetics on lipid bilayer properties and sodium channel function
,”
Eur. Biophys. J.
46
,
617
626
(
2017
).
13.
M.
Zhang
,
T.
Peyear
,
I.
Patmanidis
,
D. V.
Greathouse
,
S. J.
Marrink
,
O. S.
Andersen
, and
H. I.
Ingólfsson
, “
Fluorinated alcohols' effects on lipid bilayer properties
,”
Biophys. J.
115
,
679
689
(
2018
).
14.
R.
Kapoor
,
T. A.
Peyear
,
R. E.
Koeppe
, and
O. S.
Andersen
, “
Antidepressants are modifiers of lipid bilayer properties
,”
J. Gen. Physiol.
151
,
342
356
(
2019
).
15.
P. V.
Escribá
, “
Membrane-lipid therapy: A historical perspective of membrane-targeted therapies–from lipid bilayer structure to the pathophysiological regulation of cells
,”
Biochim Biophys Acta Biomembr.
1859
(
9 Pt. B
),
1493
1506
(
2017
).
16.
C. P.
Ferri
,
M.
Prince
,
C.
Brayne
,
H.
Brodaty
,
L.
Fratiglioni
,
M.
Ganguli
,
K.
Hall
,
K.
Hasegawa
,
H.
Hendrie
,
Y.
Huang
 et al, “
Global prevalence of dementia: A Delphi consensus study
,”
The Lancet
366
,
2112
2117
(
2005
).
17.
C. L.
Masters
,
G.
Multhaup
,
G.
Simms
,
J.
Pottgiesser
,
R.
Martins
, and
K.
Beyreuther
, “
Neuronal origin of a cerebral amyloid: Neurofibrillary tangles of Alzheimer's disease contain the same protein as the amyloid of plaque cores and blood vessels
,”
EMBO J.
4
,
2757
2763
(
1985
).
18.
J.
Hardy
and
D. J.
Selkoe
, “
The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics
,”
Science
297
,
353
356
(
2002
).
19.
D.
Eisenberg
and
M.
Jucker
, “
The amyloid state of proteins in human diseases
,”
Cell
148
,
1188
1203
(
2012
).
20.
M.
Goedert
, “
Alzheimer's and Parkinson's diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein
,”
Science
349
,
1255555
(
2015
).
21.
J.
Nasica-Labouze
,
P. H.
Nguyen
,
F.
Sterpone
,
O.
Berthoumieu
,
N.-V.
Buchete
,
S.
Coté
,
A. D.
Simone
,
A. J.
Doig
,
P.
Faller
,
A.
Garcia
,
A.
Laio
,
M. S.
Li
,
S.
Melchionna
,
N.
Mousseau
,
Y.
Mu
,
A.
Paravastu
,
S.
Pasquali
,
D. J.
Rosenman
,
B.
Strodel
,
B.
Tarus
,
J. H.
Viles
,
T.
Zhang
,
C.
Wang
, and
P.
Derreumaux
, “
Amyloid β protein and Alzheimer's disease: When computer simulations complement experimental studies
,”
Chem. Rev.
115
,
3518
3563
(
2015
).
22.
R.
Ahmed
,
M.
Akcan
,
A.
Khondker
,
M. C.
Rheinstädter
,
J. C.
Bozelli
,
R. M.
Epand
,
V.
Huynh
,
R. G.
Wylie
,
S.
Boulton
,
J.
Huang
 et al, “
Atomic resolution map of the soluble amyloid beta assembly toxic surfaces
,”
Chem. Sci.
10
,
6072
6082
(
2019
).
23.
H.
Dies
,
L.
Toppozini
, and
M. C.
Rheinstädter
, “
The interaction between amyloid-β peptides and anionic lipid membranes containing cholesterol and melatonin
,”
PLoS One
9
,
e99124
(
2014
).
24.
M. A.
Barrett
,
R. J.
Alsop
,
T.
Hauß
, and
M. C.
Rheinstädter
, “
The position of Aβ22-40 and Aβ1-42 in anionic lipid membranes containing cholesterol
,”
Membranes
5
,
824
843
(
2015
).
25.
A.
Khondker
,
R. J.
Alsop
, and
M. C.
Rheinstädter
, “
Membrane-accelerated amyloid-β aggregation and formation of cross-β sheets
,”
Membranes
7
,
49
(
2017
).
26.
N.
Dan
,
P.
Pincus
, and
S.
Safran
, “
Membrane-induced interactions between inclusions
,”
Langmuir
9
,
2768
2771
(
1993
).
27.
M. M.
Müller
,
M.
Deserno
, and
J.
Guven
, “
Interface-mediated interactions between particles: A geometrical approach
,”
Phys. Rev. E
72
,
061407
(
2005
).
28.
C. L.
Armstrong
,
E.
Sandqvist
, and
M. C.
Rheinstädter
, “
Protein-protein interactions in membranes
,”
Protein Pept. Lett.
18
,
344
353
(
2011
).
29.
J.
Tang
,
R. J.
Alsop
,
M.
Backholm
,
H.
Dies
,
A.-C.
Shi
, and
M. C.
Rheinstädter
, “
Amyloid-β 25–35 peptides aggregate into cross-β sheets in unsaturated anionic lipid membranes at high peptide concentrations
,”
Soft Matter
12
,
3165
3176
(
2016
).
30.
O. N.
Yogurtcu
and
M. E.
Johnson
, “
Cytosolic proteins can exploit membrane localization to trigger functional assembly
,”
PLoS Comput. Biol.
14
,
e1006031
(
2018
).
31.
A.
Khondker
,
R. J.
Alsop
,
S.
Himbert
,
J.
Tang
,
A.-C.
Shi
,
A. P.
Hitchcock
, and
M. C.
Rheinstädter
, “
Membrane-modulating drugs can affect the size of amyloid-β 25–35 aggregates in anionic membranes
,”
Sci. Rep.
8
,
1
16
(
2018
).
32.
I. P.
Gastaldo
,
S.
Himbert
,
U.
Ram
, and
M. C.
Rheinstädter
, “
The effects of resveratrol, caffeine, β-carotene, and epigallocatechin Gallate (EGCG) on amyloid-β25-35 aggregation in synthetic brain membranes
,”
Mol. Nutr. Food Res.
(in press) (
2020
).
33.
R.
Laxminarayan
,
A.
Duse
,
C.
Wattal
,
A. K.
Zaidi
,
H. F.
Wertheim
,
N.
Sumpradit
,
E.
Vlieghe
,
G. L.
Hara
,
I. M.
Gould
,
H.
Goossens
 et al, “
Antibiotic resistance—the need for global solutions
,”
Lancet Infect. Dis.
13
,
1057
1098
(
2013
).
34.
A.
Khondker
and
M. C.
Rheinstädter
, “
How do bacterial membranes resist polymyxin antibiotics?
,”
Commun. Biol.
3
,
77
(
2020
).
35.
G.
Humphreys
and
F.
Fleck
, “
United Nations meeting on antimicrobial resistance
,”
World Health Org. Bull. World Health Org.
94
,
638
(
2016
).
36.
A.
Khondker
,
D. J.
Malenfant
,
A. K.
Dhaliwal
, and
M. C.
Rheinstädter
, “
Carbapenems and lipid bilayers: Localization, partitioning, and energetics
,”
ACS Infect. Dis.
4
,
926
935
(
2018
).
37.
A.
Khondker
,
I.
Passos-Gastaldo
,
G. D.
Wright
, and
M. C.
Rheinstädter
, “
Membrane interactions of non-membrane targeting antibiotics: The case of aminoglycosides, macrolides and fluoroquinolones
,”
BBA Biomembr.
(in press) (
2020
).
38.
K. A.
Brogden
, “
Antimicrobial peptides: Pore formers or metabolic inhibitors in bacteria?
,”
Nat. Rev. Microbiol.
3
,
238
250
(
2005
).
39.
A.
Khondker
,
A. K.
Dhaliwal
,
S.
Saem
,
A.
Mahmood
,
C.
Fradin
,
J.
Moran-Mirabal
, and
M. C.
Rheinstädter
, “
Membrane charge and lipid packing determine polymyxin-induced membrane damage
,”
Commun. Biol.
2
,
67
(
2019
).
40.
C. J.
Kubin
,
T. M.
Ellman
,
V.
Phadke
,
L. J.
Haynes
,
D. P.
Calfee
, and
M. T.
Yin
, “
Incidence and predictors of acute kidney injury associated with intravenous polymyxin B therapy
,”
J. Infect.
65
,
80
87
(
2012
).
41.
N. A.
Berglund
,
T. J.
Piggot
,
D.
Jefferies
,
R. B.
Sessions
,
P. J.
Bond
, and
S.
Khalid
, “
Interaction of the antimicrobial peptide polymyxin B1 with both membranes of E. coli: A molecular dynamics study
,”
PLoS Comput. Biol.
11
,
e1004180
(
2015
).
42.
M. G.
Márquez
,
N. O.
Favale
,
F. L.
Nieto
,
L. G.
Pescio
, and
N.
Sterin-Speziale
, “
Changes in membrane lipid composition cause alterations in epithelial cell–cell adhesion structures in renal papillary collecting duct cells
,”
Biochim. Biophys. Acta (BBA)-Biomembr.
1818
,
491
501
(
2012
).
43.
A.
Khondker
,
R. J.
Alsop
,
A.
Dhaliwal
,
S.
Saem
,
J. M.
Moran-Mirabal
, and
M. C.
Rheinstädter
, “
Membrane cholesterol reduces polymyxin B nephrotoxicity in renal membrane analogs
,”
Biophys. J.
113
,
2016
2028
(
2017
).
44.
P.
Khakbaz
and
J. B.
Klauda
, “
Probing the importance of lipid diversity in cell membranes via molecular simulation
,”
Chem. Phys. Lipids
192
,
12
22
(
2015
).
45.
J.
McPhee
and
S.
Lewenza
, “
From pigs to patients: Transmissible, single gene-mediated resistance to colistin
,”
J. Med. Microbiol. Diagn.
5
,
221
(
2016
).
46.
L.
Guo
,
K. B.
Lim
,
C. M.
Poduje
,
M.
Daniel
,
J. S.
Gunn
,
M.
Hackett
, and
S. I.
Miller
, “
Lipid a acylation and bacterial resistance against vertebrate antimicrobial peptides
,”
Cell
95
,
189
198
(
1998
).
47.
A.
Rice
and
J.
Wereszczynski
, “
Atomistic scale effects of lipopolysaccharide modifications on bacterial outer membrane defenses
,”
Biophys. J.
114
,
1389
1399
(
2018
).
48.
M. C.
Rheinstädter
,
K.
Schmalzl
,
K.
Wood
, and
D.
Strauch
, “
Protein-protein interaction in purple membrane
,”
Phys. Rev. Lett.
103
,
128104
(
2009
).
You do not currently have access to this content.