Post on 12-Oct-2020
ISTITUTO DI GERONTOLOGIA E GERIATRIA
UNIVERSITÀ DEGLI STUDI DI PERUGIA
S.C. DI GERIATRIA
AZIENDA OSPEDALIERA DI PERUGIA
Patrizia Mecocci
Stato dell’arte sulla malattia di Alzheimer: oltre l’amiloide
1906
Back to the past
The Amyloid Hypothesis
Amyloid: always so bad?
Morris et al., Acta Neuropathol Commun, 2014
Highlights
• Amyloid-β oligomerization is not intrinsically
pathological.
• Amyloidosis emerges as an innate immune pathway.
• Pathogens can see β-amyloid deposition.
• Antimicrobial protection hypothesis of AD describes
this emerging model.
• The new model provides a rational framework for
understanding AD amyloidosis.
Aβ deposition occurs in cognitively normal subjects
Lancet Neurol , 2017
2009
… cognition and education predicted dementia but not AD- or amyloid-relatedpathologies …
Aβ deposition occurs with other proteinopathies
Mattson, Aging and Mechanisms of Disease, 2015
Each case of late-onset dementia is a unique mosaic of prototypical neuropathological landscapes
Andrade-Moraes et al., 2013
Pharmacological Reports 68, 2016
The amyloid hypothesis has failed so far clinically
“Whenever a theory appears to you as the only possible one, take this as a sign that you have neither understood the theory nor the problem which it was
intended to solve”
Karl Popper
Khalid et al. BMC Neurosci, 2018
Other hypotheses and other therapeutic actions
Senescence and Age Related Changes
Modified from Trends in Cell Biology, 2018
The Alzheimer’s continuum
Int J Mol Sci 2018
From healthy brain to brain aging insight into Age Related Changes (ARCs)
Boccardi et al., Int J Mol Sci, 2017
Aging, Alzheimer and other dementias
Neuro-vascular tracks
Montagne et al., JAMA Neurol. 2015
Biological aging represents the biomedical counterpart of the irreversible
increasing entropy of the system, where ARCs are the specific molecular
components.
All together, these changes can be considered as the result of an “energy
failure” which leads neurons and other brain cells to a progressive decline,
which ultimately limits the functional brain capacity.
Mitochondrial tracks
Ora il re Davide era vecchio e avanzato negli anni e, sebbene lo ricoprissero di panni, non riusciva a riscaldarsi.Perciò i suoi servi gli dissero: «Si cerchi per il re, nostro signore, una fanciulla vergine, che assista il re, ne abbia cura e dorma fra le sue braccia; così il re nostro signore potrà riscaldarsi».
Mitochondrial tracks
Primo Libro dei Re 1, 1-4
Mitochondrial tracks
Mecocci et al., Ann Neurol 1993Mecocci et al., Ann Neurol 1994
Pro
tein
Car
bon
yl (
% c
ontr
ol)
0
50
100
150
200
Control
AD
Pro
tein
bo
un
d H
NE
(%
Co
ntr
ol)
0
20
40
60
80
100
120
140
160
Control
AD
Sultana, Mecocci, Butterfield JAD 2011
#
Protein Carbonyls
Pro
tein
carb
onyl
s
(% c
ontr
ol)
200
150
100
50
0
*
Protein bound HNE
# p=0.03
**p=0.0006
* p=0.06
Pro
tein
bound H
NE
(% c
ontr
ol)
0
20
40
60
80
100
120
140
1603-N
itroty
rosi
ne (
% c
ontr
ol)
0
50
100
150
200
Control
AD
**
3-Nitrotyrosine
0
3-N
itro
tyro
sin
e
(% c
ontr
ol)
200
150
100
50
AD
Controls
Increased protein and lipid oxidative damage in
mitochondria from lymphocytes from AD patients
Group
OC YC MCI AD
0,60
0,80
1,00
1,20
1,40
acti
vit
tyU
/mg
pro
t.
Mangialasche et al., JAD 2015
Immuno-senescence tracks
Metabolic Tracks
Boccardi et al. 2019 under review
The potential role of insulin in the pathogenesis of dementia
Inflammation, brain insulin resistance and peripheral insulin resistance
De Felice and Ferreira Diabetes, 2014
Microbiome tracks
Healthcare 2015, 3, 898-916
Gut Microbiota: A Modulator of Brain Plasticity and Cognitive
Function in Aging
Frontiers in Aging Neuroscience 2017
Viral tracks
Aberrant Networks in Alzheimer’s Tied to Herpes Viruses
Alz Forum Courtesy of Ben Readhead
Multi-omic evidence links viral load to the molecular,
pathological, and clinical manifestations of dementia
AD: a multifactorial and heterogeneous disease
M.D. Sweeney et al. Alzheimer’s & Dementia 2019
Well we know where we’re goingBut we don’t know where we’ve beenAnd we know what we’re knowingBut we can’t say what we’ve seenAnd we’re not little childrenAnd we know what we wantAnd the future is certain
Give us time to workTalking Heads