This document summarizes research on the molecular mechanisms involved in Alzheimer's disease pathology, focusing on different conformations of beta amyloid protein (Aβ). The research found that oligomeric and monomeric forms of Aβ target synaptic terminals in a process modulated by neuronal activity and metal ions. Oligomeric Aβ was shown to rapidly induce mitochondrial dysfunction, synaptic protein release, and neuronal death. The research provides insights into how different Aβ species may contribute to Alzheimer's disease pathogenesis through distinct mechanisms.
2024 State of Marketing Report – by HubspotMarius Sescu
https://www.hubspot.com/state-of-marketing
· Scaling relationships and proving ROI
· Social media is the place for search, sales, and service
· Authentic influencer partnerships fuel brand growth
· The strongest connections happen via call, click, chat, and camera.
· Time saved with AI leads to more creative work
· Seeking: A single source of truth
· TLDR; Get on social, try AI, and align your systems.
· More human marketing, powered by robots
ChatGPT is a revolutionary addition to the world since its introduction in 2022. A big shift in the sector of information gathering and processing happened because of this chatbot. What is the story of ChatGPT? How is the bot responding to prompts and generating contents? Swipe through these slides prepared by Expeed Software, a web development company regarding the development and technical intricacies of ChatGPT!
Product Design Trends in 2024 | Teenage EngineeringsPixeldarts
The realm of product design is a constantly changing environment where technology and style intersect. Every year introduces fresh challenges and exciting trends that mold the future of this captivating art form. In this piece, we delve into the significant trends set to influence the look and functionality of product design in the year 2024.
How Race, Age and Gender Shape Attitudes Towards Mental HealthThinkNow
Mental health has been in the news quite a bit lately. Dozens of U.S. states are currently suing Meta for contributing to the youth mental health crisis by inserting addictive features into their products, while the U.S. Surgeon General is touring the nation to bring awareness to the growing epidemic of loneliness and isolation. The country has endured periods of low national morale, such as in the 1970s when high inflation and the energy crisis worsened public sentiment following the Vietnam War. The current mood, however, feels different. Gallup recently reported that national mental health is at an all-time low, with few bright spots to lift spirits.
To better understand how Americans are feeling and their attitudes towards mental health in general, ThinkNow conducted a nationally representative quantitative survey of 1,500 respondents and found some interesting differences among ethnic, age and gender groups.
Technology
For example, 52% agree that technology and social media have a negative impact on mental health, but when broken out by race, 61% of Whites felt technology had a negative effect, and only 48% of Hispanics thought it did.
While technology has helped us keep in touch with friends and family in faraway places, it appears to have degraded our ability to connect in person. Staying connected online is a double-edged sword since the same news feed that brings us pictures of the grandkids and fluffy kittens also feeds us news about the wars in Israel and Ukraine, the dysfunction in Washington, the latest mass shooting and the climate crisis.
Hispanics may have a built-in defense against the isolation technology breeds, owing to their large, multigenerational households, strong social support systems, and tendency to use social media to stay connected with relatives abroad.
Age and Gender
When asked how individuals rate their mental health, men rate it higher than women by 11 percentage points, and Baby Boomers rank it highest at 83%, saying it’s good or excellent vs. 57% of Gen Z saying the same.
Gen Z spends the most amount of time on social media, so the notion that social media negatively affects mental health appears to be correlated. Unfortunately, Gen Z is also the generation that’s least comfortable discussing mental health concerns with healthcare professionals. Only 40% of them state they’re comfortable discussing their issues with a professional compared to 60% of Millennials and 65% of Boomers.
Race Affects Attitudes
As seen in previous research conducted by ThinkNow, Asian Americans lag other groups when it comes to awareness of mental health issues. Twenty-four percent of Asian Americans believe that having a mental health issue is a sign of weakness compared to the 16% average for all groups. Asians are also considerably less likely to be aware of mental health services in their communities (42% vs. 55%) and most likely to seek out information on social media (51% vs. 35%).
AI Trends in Creative Operations 2024 by Artwork Flow.pdfmarketingartwork
This article is all about what AI trends will emerge in the field of creative operations in 2024. All the marketers and brand builders should be aware of these trends for their further use and save themselves some time!
A report by thenetworkone and Kurio.
The contributing experts and agencies are (in an alphabetical order): Sylwia Rytel, Social Media Supervisor, 180heartbeats + JUNG v MATT (PL), Sharlene Jenner, Vice President - Director of Engagement Strategy, Abelson Taylor (USA), Alex Casanovas, Digital Director, Atrevia (ES), Dora Beilin, Senior Social Strategist, Barrett Hoffher (USA), Min Seo, Campaign Director, Brand New Agency (KR), Deshé M. Gully, Associate Strategist, Day One Agency (USA), Francesca Trevisan, Strategist, Different (IT), Trevor Crossman, CX and Digital Transformation Director; Olivia Hussey, Strategic Planner; Simi Srinarula, Social Media Manager, The Hallway (AUS), James Hebbert, Managing Director, Hylink (CN / UK), Mundy Álvarez, Planning Director; Pedro Rojas, Social Media Manager; Pancho González, CCO, Inbrax (CH), Oana Oprea, Head of Digital Planning, Jam Session Agency (RO), Amy Bottrill, Social Account Director, Launch (UK), Gaby Arriaga, Founder, Leonardo1452 (MX), Shantesh S Row, Creative Director, Liwa (UAE), Rajesh Mehta, Chief Strategy Officer; Dhruv Gaur, Digital Planning Lead; Leonie Mergulhao, Account Supervisor - Social Media & PR, Medulla (IN), Aurelija Plioplytė, Head of Digital & Social, Not Perfect (LI), Daiana Khaidargaliyeva, Account Manager, Osaka Labs (UK / USA), Stefanie Söhnchen, Vice President Digital, PIABO Communications (DE), Elisabeth Winiartati, Managing Consultant, Head of Global Integrated Communications; Lydia Aprina, Account Manager, Integrated Marketing and Communications; Nita Prabowo, Account Manager, Integrated Marketing and Communications; Okhi, Web Developer, PNTR Group (ID), Kei Obusan, Insights Director; Daffi Ranandi, Insights Manager, Radarr (SG), Gautam Reghunath, Co-founder & CEO, Talented (IN), Donagh Humphreys, Head of Social and Digital Innovation, THINKHOUSE (IRE), Sarah Yim, Strategy Director, Zulu Alpha Kilo (CA).
Trends In Paid Search: Navigating The Digital Landscape In 2024Search Engine Journal
The search marketing landscape is evolving rapidly with new technologies, and professionals, like you, rely on innovative paid search strategies to meet changing demands.
It’s important that you’re ready to implement new strategies in 2024.
Check this out and learn the top trends in paid search advertising that are expected to gain traction, so you can drive higher ROI more efficiently in 2024.
You’ll learn:
- The latest trends in AI and automation, and what this means for an evolving paid search ecosystem.
- New developments in privacy and data regulation.
- Emerging ad formats that are expected to make an impact next year.
Watch Sreekant Lanka from iQuanti and Irina Klein from OneMain Financial as they dive into the future of paid search and explore the trends, strategies, and technologies that will shape the search marketing landscape.
If you’re looking to assess your paid search strategy and design an industry-aligned plan for 2024, then this webinar is for you.
5 Public speaking tips from TED - Visualized summarySpeakerHub
From their humble beginnings in 1984, TED has grown into the world’s most powerful amplifier for speakers and thought-leaders to share their ideas. They have over 2,400 filmed talks (not including the 30,000+ TEDx videos) freely available online, and have hosted over 17,500 events around the world.
With over one billion views in a year, it’s no wonder that so many speakers are looking to TED for ideas on how to share their message more effectively.
The article “5 Public-Speaking Tips TED Gives Its Speakers”, by Carmine Gallo for Forbes, gives speakers five practical ways to connect with their audience, and effectively share their ideas on stage.
Whether you are gearing up to get on a TED stage yourself, or just want to master the skills that so many of their speakers possess, these tips and quotes from Chris Anderson, the TED Talks Curator, will encourage you to make the most impactful impression on your audience.
See the full article and more summaries like this on SpeakerHub here: https://speakerhub.com/blog/5-presentation-tips-ted-gives-its-speakers
See the original article on Forbes here:
http://www.forbes.com/forbes/welcome/?toURL=http://www.forbes.com/sites/carminegallo/2016/05/06/5-public-speaking-tips-ted-gives-its-speakers/&refURL=&referrer=#5c07a8221d9b
ChatGPT and the Future of Work - Clark Boyd Clark Boyd
Everyone is in agreement that ChatGPT (and other generative AI tools) will shape the future of work. Yet there is little consensus on exactly how, when, and to what extent this technology will change our world.
Businesses that extract maximum value from ChatGPT will use it as a collaborative tool for everything from brainstorming to technical maintenance.
For individuals, now is the time to pinpoint the skills the future professional will need to thrive in the AI age.
Check out this presentation to understand what ChatGPT is, how it will shape the future of work, and how you can prepare to take advantage.
A brief introduction to DataScience with explaining of the concepts, algorithms, machine learning, supervised and unsupervised learning, clustering, statistics, data preprocessing, real-world applications etc.
It's part of a Data Science Corner Campaign where I will be discussing the fundamentals of DataScience, AIML, Statistics etc.
Time Management & Productivity - Best PracticesVit Horky
Here's my presentation on by proven best practices how to manage your work time effectively and how to improve your productivity. It includes practical tips and how to use tools such as Slack, Google Apps, Hubspot, Google Calendar, Gmail and others.
The six step guide to practical project managementMindGenius
The six step guide to practical project management
If you think managing projects is too difficult, think again.
We’ve stripped back project management processes to the
basics – to make it quicker and easier, without sacrificing
the vital ingredients for success.
“If you’re looking for some real-world guidance, then The Six Step Guide to Practical Project Management will help.”
Dr Andrew Makar, Tactical Project Management
2024 State of Marketing Report – by HubspotMarius Sescu
https://www.hubspot.com/state-of-marketing
· Scaling relationships and proving ROI
· Social media is the place for search, sales, and service
· Authentic influencer partnerships fuel brand growth
· The strongest connections happen via call, click, chat, and camera.
· Time saved with AI leads to more creative work
· Seeking: A single source of truth
· TLDR; Get on social, try AI, and align your systems.
· More human marketing, powered by robots
ChatGPT is a revolutionary addition to the world since its introduction in 2022. A big shift in the sector of information gathering and processing happened because of this chatbot. What is the story of ChatGPT? How is the bot responding to prompts and generating contents? Swipe through these slides prepared by Expeed Software, a web development company regarding the development and technical intricacies of ChatGPT!
Product Design Trends in 2024 | Teenage EngineeringsPixeldarts
The realm of product design is a constantly changing environment where technology and style intersect. Every year introduces fresh challenges and exciting trends that mold the future of this captivating art form. In this piece, we delve into the significant trends set to influence the look and functionality of product design in the year 2024.
How Race, Age and Gender Shape Attitudes Towards Mental HealthThinkNow
Mental health has been in the news quite a bit lately. Dozens of U.S. states are currently suing Meta for contributing to the youth mental health crisis by inserting addictive features into their products, while the U.S. Surgeon General is touring the nation to bring awareness to the growing epidemic of loneliness and isolation. The country has endured periods of low national morale, such as in the 1970s when high inflation and the energy crisis worsened public sentiment following the Vietnam War. The current mood, however, feels different. Gallup recently reported that national mental health is at an all-time low, with few bright spots to lift spirits.
To better understand how Americans are feeling and their attitudes towards mental health in general, ThinkNow conducted a nationally representative quantitative survey of 1,500 respondents and found some interesting differences among ethnic, age and gender groups.
Technology
For example, 52% agree that technology and social media have a negative impact on mental health, but when broken out by race, 61% of Whites felt technology had a negative effect, and only 48% of Hispanics thought it did.
While technology has helped us keep in touch with friends and family in faraway places, it appears to have degraded our ability to connect in person. Staying connected online is a double-edged sword since the same news feed that brings us pictures of the grandkids and fluffy kittens also feeds us news about the wars in Israel and Ukraine, the dysfunction in Washington, the latest mass shooting and the climate crisis.
Hispanics may have a built-in defense against the isolation technology breeds, owing to their large, multigenerational households, strong social support systems, and tendency to use social media to stay connected with relatives abroad.
Age and Gender
When asked how individuals rate their mental health, men rate it higher than women by 11 percentage points, and Baby Boomers rank it highest at 83%, saying it’s good or excellent vs. 57% of Gen Z saying the same.
Gen Z spends the most amount of time on social media, so the notion that social media negatively affects mental health appears to be correlated. Unfortunately, Gen Z is also the generation that’s least comfortable discussing mental health concerns with healthcare professionals. Only 40% of them state they’re comfortable discussing their issues with a professional compared to 60% of Millennials and 65% of Boomers.
Race Affects Attitudes
As seen in previous research conducted by ThinkNow, Asian Americans lag other groups when it comes to awareness of mental health issues. Twenty-four percent of Asian Americans believe that having a mental health issue is a sign of weakness compared to the 16% average for all groups. Asians are also considerably less likely to be aware of mental health services in their communities (42% vs. 55%) and most likely to seek out information on social media (51% vs. 35%).
AI Trends in Creative Operations 2024 by Artwork Flow.pdfmarketingartwork
This article is all about what AI trends will emerge in the field of creative operations in 2024. All the marketers and brand builders should be aware of these trends for their further use and save themselves some time!
A report by thenetworkone and Kurio.
The contributing experts and agencies are (in an alphabetical order): Sylwia Rytel, Social Media Supervisor, 180heartbeats + JUNG v MATT (PL), Sharlene Jenner, Vice President - Director of Engagement Strategy, Abelson Taylor (USA), Alex Casanovas, Digital Director, Atrevia (ES), Dora Beilin, Senior Social Strategist, Barrett Hoffher (USA), Min Seo, Campaign Director, Brand New Agency (KR), Deshé M. Gully, Associate Strategist, Day One Agency (USA), Francesca Trevisan, Strategist, Different (IT), Trevor Crossman, CX and Digital Transformation Director; Olivia Hussey, Strategic Planner; Simi Srinarula, Social Media Manager, The Hallway (AUS), James Hebbert, Managing Director, Hylink (CN / UK), Mundy Álvarez, Planning Director; Pedro Rojas, Social Media Manager; Pancho González, CCO, Inbrax (CH), Oana Oprea, Head of Digital Planning, Jam Session Agency (RO), Amy Bottrill, Social Account Director, Launch (UK), Gaby Arriaga, Founder, Leonardo1452 (MX), Shantesh S Row, Creative Director, Liwa (UAE), Rajesh Mehta, Chief Strategy Officer; Dhruv Gaur, Digital Planning Lead; Leonie Mergulhao, Account Supervisor - Social Media & PR, Medulla (IN), Aurelija Plioplytė, Head of Digital & Social, Not Perfect (LI), Daiana Khaidargaliyeva, Account Manager, Osaka Labs (UK / USA), Stefanie Söhnchen, Vice President Digital, PIABO Communications (DE), Elisabeth Winiartati, Managing Consultant, Head of Global Integrated Communications; Lydia Aprina, Account Manager, Integrated Marketing and Communications; Nita Prabowo, Account Manager, Integrated Marketing and Communications; Okhi, Web Developer, PNTR Group (ID), Kei Obusan, Insights Director; Daffi Ranandi, Insights Manager, Radarr (SG), Gautam Reghunath, Co-founder & CEO, Talented (IN), Donagh Humphreys, Head of Social and Digital Innovation, THINKHOUSE (IRE), Sarah Yim, Strategy Director, Zulu Alpha Kilo (CA).
Trends In Paid Search: Navigating The Digital Landscape In 2024Search Engine Journal
The search marketing landscape is evolving rapidly with new technologies, and professionals, like you, rely on innovative paid search strategies to meet changing demands.
It’s important that you’re ready to implement new strategies in 2024.
Check this out and learn the top trends in paid search advertising that are expected to gain traction, so you can drive higher ROI more efficiently in 2024.
You’ll learn:
- The latest trends in AI and automation, and what this means for an evolving paid search ecosystem.
- New developments in privacy and data regulation.
- Emerging ad formats that are expected to make an impact next year.
Watch Sreekant Lanka from iQuanti and Irina Klein from OneMain Financial as they dive into the future of paid search and explore the trends, strategies, and technologies that will shape the search marketing landscape.
If you’re looking to assess your paid search strategy and design an industry-aligned plan for 2024, then this webinar is for you.
5 Public speaking tips from TED - Visualized summarySpeakerHub
From their humble beginnings in 1984, TED has grown into the world’s most powerful amplifier for speakers and thought-leaders to share their ideas. They have over 2,400 filmed talks (not including the 30,000+ TEDx videos) freely available online, and have hosted over 17,500 events around the world.
With over one billion views in a year, it’s no wonder that so many speakers are looking to TED for ideas on how to share their message more effectively.
The article “5 Public-Speaking Tips TED Gives Its Speakers”, by Carmine Gallo for Forbes, gives speakers five practical ways to connect with their audience, and effectively share their ideas on stage.
Whether you are gearing up to get on a TED stage yourself, or just want to master the skills that so many of their speakers possess, these tips and quotes from Chris Anderson, the TED Talks Curator, will encourage you to make the most impactful impression on your audience.
See the full article and more summaries like this on SpeakerHub here: https://speakerhub.com/blog/5-presentation-tips-ted-gives-its-speakers
See the original article on Forbes here:
http://www.forbes.com/forbes/welcome/?toURL=http://www.forbes.com/sites/carminegallo/2016/05/06/5-public-speaking-tips-ted-gives-its-speakers/&refURL=&referrer=#5c07a8221d9b
ChatGPT and the Future of Work - Clark Boyd Clark Boyd
Everyone is in agreement that ChatGPT (and other generative AI tools) will shape the future of work. Yet there is little consensus on exactly how, when, and to what extent this technology will change our world.
Businesses that extract maximum value from ChatGPT will use it as a collaborative tool for everything from brainstorming to technical maintenance.
For individuals, now is the time to pinpoint the skills the future professional will need to thrive in the AI age.
Check out this presentation to understand what ChatGPT is, how it will shape the future of work, and how you can prepare to take advantage.
A brief introduction to DataScience with explaining of the concepts, algorithms, machine learning, supervised and unsupervised learning, clustering, statistics, data preprocessing, real-world applications etc.
It's part of a Data Science Corner Campaign where I will be discussing the fundamentals of DataScience, AIML, Statistics etc.
Time Management & Productivity - Best PracticesVit Horky
Here's my presentation on by proven best practices how to manage your work time effectively and how to improve your productivity. It includes practical tips and how to use tools such as Slack, Google Apps, Hubspot, Google Calendar, Gmail and others.
The six step guide to practical project managementMindGenius
The six step guide to practical project management
If you think managing projects is too difficult, think again.
We’ve stripped back project management processes to the
basics – to make it quicker and easier, without sacrificing
the vital ingredients for success.
“If you’re looking for some real-world guidance, then The Six Step Guide to Practical Project Management will help.”
Dr Andrew Makar, Tactical Project Management
Beginners Guide to TikTok for Search - Rachel Pearson - We are Tilt __ Bright...
Dissertation Talk
1. Molecular Mechanisms
Involved in
Alzheimer’s Disease Pathology
Atul Deshpande, Ph.D
P.I.: Dr. Jorge Busciglio
Dept. of Neurobiology and Behavior
University of California, Irvine
2. Background: Prevalence
Alzheimer’s Disease is the leading cause of
dementia among elderly people.
An estimate of 12% Americans over the age
of 65 and almost half above the age of 85
have AD (~5 million).
Alzheimer’s Disease is the 3rd most
expensive disease to treat, costing the society
close to $100 billion annually.
AD is a progressive disorder beginning with
memory deficits and leading to dementia.
3. Background: Etiology
The disease is characterized by two main lesions:
Amyloid Plaques Neurofibrillary Tangles
Synaptic loss precedes neuronal loss
The neurodegeneration occurs in several brain
areas including cortex, hippocampus and basal
forebrain.
5. This Talk...
Aß -
• Brief Background: Different conformations
• Results
• Effect of different conformations of Aß on HCN
• Role in AD pathogenesis
• Conclusions with possible model system
for mechanism(s) of neurotoxicity
6. Beta Amyloid (Aß): main component of plaques
Two types of Aß deposits are found, a) the dense core neuritic plaques
consisting of fibrillar insoluble Aß, and b) the diffuse plaques
A 40-42 amino acid peptide product of ß and γ secretase mediated
cleavage of amyloid precursor protein (APP)
Fibrilization of Aß is
preceded by multiple
conformational changes but
the pathways to
oligomerization and
fibrilization can be
independent (Necula et. al.,
2007)
7. Different Conformations of ß-amyloid
Aβ42 Monomers
Aß Derived Diffusible Ligands (ADDLs) Aβ42 Oligomer (AβO)
AFM EM
O
L
EM
Aß*56 M
O
G
I R
E S
(Lambert et. al., 1998) Demuro et. al. 2004
Annular Protofibrils
Protofibrils
EM
Aβ42 Fibrils (AβF)
8. Different Conformations of ß-amyloid
Aβ42 Monomers
Aß Derived Diffusible Ligands (ADDLs) Aβ42 Oligomer (AβO)
AFM EM
O
L
EM
Aß*56 M
O
G
I R
Soluble
E S
(Lambert et. al., 1998) forms Demuro et. al. 2004
of Aß Annular Protofibrils
Protofibrils
EM
Aβ42 Fibrils (AβF)
11. Soluble Aß…
M.W.
AßO and ADDLs are found
100
AßO (~90kd) in the brains of AD patients
75 and have been found to…
50 a) Induce acute
electrophysiological changes,
25 b) Inhibit long-term potentiation
20
ADDLs (~17-24kd)
and impair memory function
15
c) Permeabilize cell membrane
10 and lead to influx of calcium,
Monomer (~4.5kd)
d) Affect neuronal viability
12. Objective of this study…
Characterization of soluble oligomeric amyloid
has raised the possibility that different Aß
conformations may contribute to AD pathology
via different mechanism(s)
To characterize the toxicity of different Aß species:
We tested side by side the effect of well
characterized AßO, ADDLs and Aß fibrils in
Human Cortical Neurons.
13. Experimental Model: Human
Cortical Neurons (HCN)
Target Cells in Alzheimer’s Disease
Similar profiles of protein expression to the adult human brain
(e.g. tau, etc.).
HCN (0 DIV) HCN (20 DIV)
17. Aß42f induce neuronal dystrophy, synaptic
loss and modest cell death over an
extended period of time
Control AβF (20μM; 10 Days)
Tau
Aβ
(Grace et.al;2002; Grace and Busciglio; 2003)
18. Soluble Aß colocalizes with synaptic markers in HCN
60
% colocolization
40
20
0
5 30 60 min
AßO are rapidly targeted to synaptic terminals
21. AßO induce rapid mitochondrial alterations
AßO at 5µM very rapidly activate an apoptotic cascade in HCN
22. Soluble AßOs induce translocation of cyt. c and AIF
from mitochondria to the cytoplasmic compartment
23. AßO neurotoxicity under normal and low extracellular calcium
After 12 hr with 5µM AßO…
Regular Low Ca+2
medium
↓ mitochondrial oxido- No Change
reductase activity
↑ activated caspases No Change
3/7
↑ LDH in supernatant No Change
After 24 hr with 5µM AßO…
Regular Low Ca+2
medium
↓ mitochondrial oxido- ↓ mitochondrial oxido-
reductase activity reductase activity
↑ activated caspases ↑ activated caspases
3/7 3/7
↑ LDH in supernatant ↑ LDH in supernatant
AßO neurotoxicity is accelerated by calcium influx
24. Incubation with AßO at lower concentrations
Lower concentrations of AßO showed chronic mitochondrial
alterations but no cell death
25. Summary…
MMP: Mitochondrial Membrane Potential
ATP: Energy currency of the Neurons
MTS: Measure of efficiency of some of the key enzymes of
the electron transport chain
Cyt.C/AIF: Cytochrome C/Apoptosis Inducing Factor
LDH: Lactate Dehydrogenase released/leaked into culture media
26. Mechanisms of AßO synaptic targeting
a) Activity dependent AßO targeting?
b) Role of metal ions?
c) Endocytosis?
d) Binding to specific receptor(s)?
27. Methods:
Two different culture systems were used:
1. Rat hippocampal organotypic cultures: allows the study of well
characterized structures and synapses
2. HCN: allows the tracking of individual endocytic vesicles
Colocalization studies were carried out using three different antibodies
(A11, NU2 and M69)
Z-sections were reconstructed using a rendering software to visualize
the colocalization of AßO and synaptophysin
28. Neuronal activity modulates localization of
AßO to synaptic terminals
Stimulation: 5min
20 mM KCl
100µM glutamate
Inhibition: 15 min
2µM TTX
29. Neuronal activity modulates localization of
AßO to synaptic terminals
Stimulation: 5min
20 mM KCl
100µM glutamate
Inhibition: 15 min
2µM TTX
min
30. Role of metal-ions:
✓ Metal ions, especially Cu+2 and Zn+2, are released at
synaptic terminals during synaptic activity
✓ Aß binds to Cu+2 and Zn+2 with very high affinity (K1(Zn):
7; K1(Cu): 8.9)
✓ Thus, released metal-ions in the synaptic cleft could
“attract” AßO to the synaptic terminals
31. Clioquinol:
Effects of Oral Treatment of 15-Month-Old APP2576
Transgenic Mice with Clioquinol (from Cherny et. al., 2001)
5-chloro-7-iodo-quinolin-8-ol
Clioquinol, iodochlorhydroxyquin, is a metal-protein- attenuating compound (MPAC)
Clioquinol topical is an antifungal and antibacterial medication
Clioquinol is a chelator that allows the sequesstration of Zn/Cu-binding compounds,
including Aß
A phase II trial reports that AD patients on the drug had a slower cognitive decline
than patients on placebo (Ritchie CW, et. al., 2004)
Also effective to reduce htt accumulation in a Huntington’s mouse model
32. Effect of metal-ion chelation by clioquinol
on synaptic localization of AßO
Metal ions appear to be involved in synaptic
localization of AßO
33. Analysis of AßO endocytosis at
synaptic terminals
AßO are not
endocytosed
at synaptic
terminals
34. NMDAR activation appears to mediate
synaptic localization of AßO
• Recent studies have suggested role of specific receptors in AßO
mediated neurotoxicity
• NMDA receptor activity was inhibited using APV, memantine and
ifenprodil.
• AMPA receptor activity was inhibited using CNQX
35. NMDAR activation appears to mediate
synaptic localization of AßO
• Recent studies have suggested role of specific receptors in AßO
mediated neurotoxicity
• NMDA receptor activity was inhibited using APV, memantine and
ifenprodil.
• AMPA receptor activity was inhibited using CNQX
AßO neurotoxicity appears to be mediated via
NMDA receptor
36. Oligomeric specific antibody labeling
colocalizes with synaptic markers in the
AD Brain
8 NL and 10 AD cases were
analyzed:
AßO labeling
colocalized in 8 of 10
AD cases
Weak AßO labeling observed
in 2 of 8 NL cases
37. Oligomeric specific antibody labeling
colocalizes with synaptic markers in the
AD Brain
8 NL and 10 AD cases were
analyzed:
AßO labeling
colocalized in 8 of 10
AD cases
Weak AßO labeling observed
in 2 of 8 NL cases
40. Mechanisms of AßO synaptic targeting
Activity dependent AßO targeting ✓
Role of metal ions ✓
41. Mechanisms of AßO synaptic targeting
Activity dependent AßO targeting ✓
Role of metal ions ✓
Endocytosis X
42. Mechanisms of AßO synaptic targeting
Activity dependent AßO targeting ✓
Role of metal ions ✓
Endocytosis X
Binding to specific receptor(s) ?
43. Working Model for AßO mediated molecular
mechanism(s) in AD pathogenesis
44. Conclusion:
AßO affect synaptic plasticity and neuronal function
Multiple Aß species capable of deleterious effects at
multiple levels coexist in the AD brain.
Therapeutic strategies to address Aß-mediated
neurotoxicity will require a refined multimodal approach.
46. Alzheimer’s Disease Lesions:
Amyloid Plaques Neurofibrillary Tangles
Multimeric and oligomeric tau and Aß species appear to have a
significant role in AD pathology
Establishing how the load of Aß-soluble species changes during
disease progression
Exploring the role of specific receptors in AßO mediated
neurotoxicity and relationship of AßO with post synaptic
receptors in the AD brain
47. Acknowledgements
P.I: Dr. Jorge Busciglio
Supported by funding from NIH and Alzheimer’s Association, Hilblom Foundation and ADRC, UCI
48. Acknowledgements
P.I: Dr. Jorge Busciglio
Lab Members
Dr. Gustavo Pigino
Ale Pelsman
Pablo Helguera
Khin Win
Michael Hanna
Rosa Resende
Jackie Selgie
Octavio Garcia
Ardy Rahman
Supported by funding from NIH and Alzheimer’s Association, Hilblom Foundation and ADRC, UCI
49. Acknowledgements
P.I: Dr. Jorge Busciglio
Lab Members Collaborators:
Dr. Gustavo Pigino Dr. Charlie Glabe
Ale Pelsman Glabe Lab
Special Thanks
Pablo Helguera Dr. Frank LaFerla
Dr. Raju Metherate
Khin Win LaFerla Lab Dr. Hideki Kawai
Michael Hanna Dr. Katumi Sumikawa Dr. John Marshal
Rosa Resende Dr. Ian Parker Dr. Amit Deshpande
Jackie Selgie Dr. Angelo Demuro
Octavio Garcia Dr. Marcelo Wood
Ardy Rahman Dr. Gustavo Pigino, UIC
Dr. Scott Brady, UIC
Supported by funding from NIH and Alzheimer’s Association, Hilblom Foundation and ADRC, UCI
Editor's Notes
common symptom pattern begins with gradually worsening difficulty remembering new information. This is because disruption of brain cells usually begins in
regions involved in forming new memories. As damage spreads, individuals also experience confusion, disorganized thinking, impaired judgment, trouble expressing themselves and disorientation.
a person has a problem with memory, language or another essential cognitive function serious enough to be noticeable to others and to show up on tests, but not severe enough to interfere with daily life. Some, but not all, people with MCI develop dementia over time, especially when their primary area of difficulty involves memory
Deshpande et al submitted manuscript
New slide for 4R
Dosage and time
Oligomer panel as a separate panel of animation
Oligomer panel as a separate panel of animation
Bigger panels for this slide… chronic changes in mitochondrial function, but no cell death
Previous studies indicate that Aß soluble species are toxic at low concentrations, reduce synaptic density, induce cognitive dysfunction, and inhibit long-term potentiation (Lambert et al., 1998; Hartley et al., 1999; Dahlgren et al., 2002; Walsh et al., 2002a; Wang et al., 2002).
We just saw what happens once AßO are at the synapses/near cell surface…
Change image color!!! Either one…
Change image color!!! Either one…
Change image color!!! Either one…
Change image color!!! Either one…
Change image color!!! Either one…
Change image color!!! Either one…
We just saw what happens once AßO are at the synapses/near cell surface…
We just saw what happens once AßO are at the synapses/near cell surface…
We just saw what happens once AßO are at the synapses/near cell surface…
We just saw what happens once AßO are at the synapses/near cell surface…
We just saw what happens once AßO are at the synapses/near cell surface…
We just saw what happens once AßO are at the synapses/near cell surface…
We just saw what happens once AßO are at the synapses/near cell surface…
We just saw what happens once AßO are at the synapses/near cell surface…
About 40 new cases of AD have developed and hopefully we are a step closer in understanding the mechanisms underlying AD pathology and to developing preventive therapeutics.