2. The classical beta amyloid cascade hypothesis
Basics and issues
• Beta amyloid protein is accumulating in the brain and
finally produces deposits as amyloid plaques
• Amyloid aggregates are toxic and expected to initiate the
neurophathological chain of events mediated through
receptors and also possibly via Tau
• Ultimately these events are leading to AD
➢Major weakness:
• The current amyloid cascade hypothesis basically ignores
the physiological role of Aβ monomer in synaptic processes
2
3. The classical beta amyloid cascade hypothesis:
Lowering beta amyloid production failed in the clinic
➢Lowering Amyloid beta production levels via Gamma-
or Beta-Secretase inhibitors or immunotherapy will
reduce amyloid deposits
➢ This approach has led to many disappointments in
clinical trials:
− Gamma secretase inhibitors failed and produced
cognitive side effects
− Beta secretase inhibitors have not produced a
significant clinical effect so far; (pre)clinical
evidence for synaptic impairment at higher doses
− Pan Abeta antibodies have shown poor efficacy, if at
all
3
4. 4
The confusion around “Amyloid beta, Aβ“
Three very different types of proteins sharing the same
name
Aβ Amyloid beta (x-y)
Aβ
isoform
Physiologica
l Aβ
monomer
Misfolded Aβ (Soluble Oligomers) Fibrillar Aβ
3D
structure
Metastable
unknown*
Core structure by NMR X-ray
structure
Varieties 1-40,1-42 x-40,42**, AA-Modifications (e.g.
pGlu),
Lipid complexes and combinations,
but shared conserved 20-30 epitope
1-40,1-42
• Categorizing between „the good Aβ“ , „the early neurotoxic Aβ
(soluble oligomers)“ and „the fibril type Aβ (plaques)“
* unstable outside
CSF, Plasma
** x =1-4
Early
pathology
fast
Protofibril/fibril pathology, slow
?
5. Revising the amyloid cascade hypothesis:
Aβ monomer is essential for synaptic processes
5
Item Key data Paper
Synaptic
processes
Endogenously released Aβ peptides regulate synaptic
transfer at single presynaptic terminals and synaptic
connections in rodent hippocampal cultures and
slices
E. Abramov, Nature
Neuroscience 2009
Synaptic
activity
Inhibiting neuronal activity by TTX (EEG) decreases
ISF Aβ levels
Ciritto et al., Neuron 2005
Procognitive
effects
• Low doses of monomeric Abeta (administered
ICV) improves cognitive behavior in non TG mice
• Anti monomer Aβ antibody impairs cognitive
behavior in non TG mice
• Aβ monomer is essential for LTP
• Impaired learning by anti sense Aβ
Morey et al., Journal of
Alzheimer’s Disease 2010
APP KO mice • Impaired LTP
• Poor performance in spatial memory tasks
• Reduced synapses
Dawson GR, et al Neuroscience
1999, Seebrook et al.,
Neuropharmacology 1999
PS1 deficient
mice
• Reduced Abeta levels
• Impaired LTP
Morton RA, Neurosci Lett ,,
2002
6. Revising the amyloid cascade hypothesis:
The Beta Amyloid Dysfunction (BAD) hypothesis in AD
• Physiological Beta amyloid is a key molecule in synaptic
transmission. Its biogenesis and turnover is an essential
physiological process conserved in neurons of vertebrates
• Maintaining sufficient synaptic Aβ levels is essential and extremely
complex: Aβ is a metastable peptide produced at high rates and
high turnover in neurons
• Aβ pathophysiology is assumed to start, when the high energy
dependent Aβ formation and metabolism process is disturbed.
• Impairment in the Aβ turnover process creates: 1. early misfolded
neuropathogenic species and 2. reduced synaptic physiological Aβ
levels:
→ Beta Amyloid Dysfunction (BAD) Hypothesis
6
7. The Beta Amyloid Dysfunction Hypothesis
1. The Beta Amyloid physiological process
7
Aa
a
Aa
A Synaptic
transmission
Synaptic processes in
neurons
Neuronal
function
1. Aβ monomer is maintained at synaptic processes in a proper
concentration and folding
BACE
Aβ pools in CSF and Plasma are gold
standards for clean Aβ monomer
8. The Beta Amyloid Dysfunction Hypothesis (BAD)
2. The Beta Amyloid patho-physiological process
8
Aa
a
Aa
A
Dysregulation of Aβ
pathway
2. Disease process through Aβ misfolding: early misfolded Aβ species
emerge and synaptic levels of physiological Aβ are reduced
Synaptic deficits via
1. Aβ oligomers↑
2. Aβ monomer↓
BACE
Neuronal
dysfunction
via Aβ
oligomer
effects on
promiscuous
receptors
9. The Beta Amyloid Dysfunction Hypothesis (BAD)
3. Compensation worsens pathology: a vicious circle
9
Aa
a
Aa
A
BACE
3. Compensatory mechanisms in early Aβ pathology : APP processing
enhanced to substitute synaptic Aβ monomer deficits
compensatory APP processing via
upregulation of BACE to restore Aβ
monomer mediated synaptic
function
Dysregulation of Aβ
pathway
Synaptic deficits
via
1. Aβ oligomers↑
2. Aβ monomer↓
Neuronal
dysfunction
via Aβ
oligomer
effects on
promiscuous
receptors
10. The Beta Amyloid Dysfunction Hypothesis (BAD)
Immunotherapy reverses Aβ dysregulation
10
Aa
a
Aa
A
BACE
Neuronal
dysfunction
via Aβ
oligomer
effects on
promiscuous
receptors
Synaptic deficits
via
1. Aβ oligomers↓
2. Aβ monomer↑
Aβ pathway normalized
Removing Aβ misfolded species in neurons by highly conformer specific
antibodies should reinstate normal Aβ processing and rescue neurons
Y
complex
eliminated
X
compensatory APP processing via
upregulation of BACE to restore Aβ
monomer mediated synaptic
function
X
11. The pathology starts inside the neuron
Intraneuronal Aβ1-42 accumulation
11
Findings Tools Paper
Aβ 4-42 early intraneural
accumulation and rescue of
toxicity
NT4X-167, a novel monoclonal
antibody demonstrated
intraneural staining; 5XFAD
mice
Antonios , G.et al. Acta
Neuropathologica
Communications 2013
Genetic and pharmacological
evidence of intraneuronal Aβ
accumulation in APP
transgenic mice
BACE-1 deficient APP
transgenic mice: neither Aβ
production nor intraneuronal
immunostaining.
O.Philipson et al.
FEBS Letters 2009
Both intraneuronal Aβ
accumulation and
extracellular Aβ deposition
was demonstrated
MOAB-2 antibody detects N-
terminal Aβ;
5XFAD mice
Youmans, KL et al.; Mol
Neurodegener., 2012
Human APOE genotype affects
Intraneuronal Aβ1-42
Accumulation
Lentiviral Gene Transfer Model W.Zhao et al. Human
Molecular Genetics, 2014
12. The Beta amyloid cascade versus BAD hypothesis
- Major differences and therapeutic implications (I)
12
Item Beta amyloid cascade
Hypothesis
Beta amyloid dysfunction (BAD)
Hypothesis
Physiological Aβ
monomer
precursor for aggregated Aβ to be preserved at sufficient
concentrations in synaptic processes
Pathophysiology amyloid deposits
(protofibrils, fibrils)
misfolded species formed in neurons
Reduced Aβ CSF
levels in AD
difficult to explain explained by interdependent and
opposite proteins: Aβ monomer vs. Aβ
oligomers
APP KO mice mice are viable age dependent learning deficits indicate
that Aβ is essential in synaptic processes
Genetic AD link
in fAD
not all PS mutations
explained by Aβ
overproduction
all PS mutations interfere with
maintainance of regular physiological
Aβ monomer
Aβ lowering
strategy?
Yes
BACE and Gamma-Secretase
inhibitors lower aggregation
propensity
No
1. risk of cognitive deficits through
lowering physiological Aβ monomer at
synaptic sites
2. Antibody consumption by excess
13. The Beta amyloid cascade versus BAD hypothesis
- Major differences and therapeutic implications (II)
13
Item Beta amyloid cascade
Hypothesis
Beta amyloid dysfunction (BAD)
Hypothesis
Gamma
secretase
inhibitors
+
failure explained by Notch or
AICD mediated side effects
- (+) for modulators
inferior with role of physiological Aβ
synaptic function; Aβ modulators do not
change overall β concentration
BACE Inhibitors +
impaired synaptic plasticity and
cognition in adult rats (high dose)
-
inferior with role of physiological Aβ
synaptic function
Pan Aβ
immunotherapy
+
dose limiting side effects (e.g
ARIA)
-
1. inferior with role of physiological Aβ
synaptic function
2. consumption of Mabs in plasma avoid
CNS exposure
Early misfolded
Aβ oligomer
specific
immunotherapy
+
a recent antibody solved one of
two problems: monomer
selectivity but not plaque
dissolution (ARIA)
+
neutralizing low fraction of pathogenic
misfolded Aβ species generated during
impaired neuronal Aβ processing
14. The Beta Amyloid Dysfunction (BAD) hypothesis in AD
- Immunotherapy via early misfolded Aβ specific Ab´s
• Aβ deposits in parenchyma and plaques are not the
primary target for the treatment of Aβ pathology in AD
• An effective immunotherapy treatment requires
presence of conformer selective antibodies which
remove misfolded species thereby restoring
physiological Aβ function
14