Related Experiment Video

Updated: May 13, 2026

Preparation of Oligomeric β-amyloid1-42 and Induction of Synaptic Plasticity Impairment on Hippocampal Slices
04:41

Preparation of Oligomeric β-amyloid1-42 and Induction of Synaptic Plasticity Impairment on Hippocampal Slices

Published on: July 14, 2010

An intracellular threonine of amyloid-β precursor protein mediates synaptic plasticity deficits and memory loss

Franco Lombino1, Fabrizio Biundo, Robert Tamayev

  • 1Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America.

Plos One
|March 2, 2013
PubMed

Insights

Phosphorylation of Amyloid-ß Precursor Protein (APP) at Thr(668) contributes to dementia. Preventing this phosphorylation in APP(TA) mice rescues memory and synaptic deficits, suggesting a therapeutic target.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Familial Alzheimer's Disease (FAD) and Danish Dementia (FDD) are linked to mutations in Amyloid-ß Precursor Protein (APP) and BRI2/ITM2b genes.
  • APP processing generates amyloid-beta (Aß) and other fragments, including the carboxyl-terminal fragment ß-CTF.
  • ß-CTF, not Aß, is implicated in memory and synaptic plasticity deficits observed in a knock-in mouse model of FDD.

Purpose of the Study:

  • To investigate the pathogenic role of the ß-CTF fragment of APP.
  • To examine the specific contribution of Thr(668) phosphorylation within ß-CTF to dementia pathogenesis.
  • To determine if preventing Thr(668) phosphorylation can ameliorate cognitive and synaptic deficits.

Main Methods:

  • Creation of a knock-in mouse model (APP(TA) mice) with a Thr(668)Ala mutation to prevent phosphorylation at this site.
  • Utilizing a knock-in mouse model of FDD (FDDKI mice) exhibiting memory and synaptic plasticity deficits.
  • Comparing cognitive and synaptic function between wild-type, APP(TA), FDDKI, and FDDKI mice with the APP(TA) mutation.

Main Results:

  • APP(TA) mice lacking Thr(668) phosphorylation did not develop memory or synaptic plasticity deficits.
  • The Thr(668)Ala mutation in APP(TA) mice prevented the development of deficits seen in FDDKI mice.
  • These findings implicate the carboxyl-terminal APP domain, specifically Thr(668) phosphorylation, in dementia pathology.

Conclusions:

  • Phosphorylation of APP at Thr(668) plays a critical role in the pathogenesis of dementia.
  • Preventing Thr(668) phosphorylation is a potential therapeutic strategy for FAD, FDD, and potentially other dementias.
  • Targeting the carboxyl-terminal APP domain offers a novel therapeutic avenue for neurodegenerative diseases.

More Related Videos

Imaging the Intracellular Trafficking of APP with Photoactivatable GFP07:55

Imaging the Intracellular Trafficking of APP with Photoactivatable GFP

Published on: October 17, 2015

Visualizing Axonal Growth Cone Collapse and Early Amyloid β Effects in Cultured Mouse Neurons06:23

Visualizing Axonal Growth Cone Collapse and Early Amyloid β Effects in Cultured Mouse Neurons

Published on: October 30, 2018

Related Concept Videos

Alzheimer Disease ll: Pathophysiology01:23

Alzheimer Disease ll: Pathophysiology

Alzheimer disease involves structural changes in the brain that begin long before symptoms appear. The most distinctive features are extracellular neuritic plaques and intracellular neurofibrillary tangles.Neuritic plaques form in the cerebral cortex and around blood vessels. These plaques contain a dense core of beta-amyloid (Aβ)—a toxic protein fragment that clumps outside neurons. The core is surrounded by damaged neuronal extensions, as well as reactive astrocytes and microglia. Abnormal...
Amyloid Fibrils03:03

Amyloid Fibrils

Amyloid fibrils are aggregates of misfolded proteins.  Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils. 
Amyloid deposits were observed as early as 1639 in the liver and the spleen.   In 1854, Rudolph Virchow performed iodine staining, normally used to...
Amyloid Fibrils03:03

Amyloid Fibrils

Amyloid fibrils are aggregates of misfolded proteins.  Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils. 
Amyloid deposits were observed as early as 1639 in the liver and the spleen.   In 1854, Rudolph Virchow performed iodine staining, normally used to...
Role of Neurotransmitters in Memory01:23

Role of Neurotransmitters in Memory

Neurotransmitters are integral to the brain's communication system, enabling neurons to transmit signals across synapses. This chemical exchange underpins various cognitive functions, including memory processes. The role of neurotransmitters in memory is multifaceted, influencing the encoding, consolidation, and retrieval of memories through their action on different neural circuits.
 Glutamate and Synaptic Plasticity
Glutamate, the brain's main excitatory neurotransmitter, is critical for...
Long-term Depression01:03

Long-term Depression

Long-term depression, or LTD, is one of the ways by which synaptic plasticity—changes in the strength of chemical synapses—can occur in the brain. LTD is the process of synaptic weakening that occurs over time between pre and postsynaptic neuronal connections. The synaptic weakening of LTD works in opposition to synaptic strengthening by long-term potentiation (LTP) and together are the main mechanisms that underlie learning and memory.
Calcium Ion Concentration Mechanism
If over time, all...
Long-term Depression01:05

Long-term Depression

Long-term depression, or LTD, is one of the ways by which synaptic plasticity—changes in the strength of chemical synapses—can occur in the brain. LTD is the process of synaptic weakening that occurs over time between pre and postsynaptic neuronal connections. The synaptic weakening of LTD works in opposition to synaptic strengthening by long-term potentiation (LTP) and together are the main mechanisms that underlie learning and memory.