Presenilin Mutations Stall Endosomal Transport, Swell Axons
In neurons lacking PS1, late endosomes get bogged down by imbalanced calcium. This puts kinases in a tizzy, slows motor proteins, and makes neurites dystrophic.
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Aggregates of TDP-43 in Muscle—Potential ALS Marker?
TDP-43 inclusions in intramuscular nerve bundles, paired with clinical criteria, may enable diagnoses at early stages of ALS.
Two ApoE Mutations Decrease Risk for Alzheimer's Disease
A case-control study of half a million people nabbed the variants. Both are rare, lie in the C-terminal lipid-binding domain, and one neutralizes ApoE4.
LRRK2 Inhibitor Hits Target, Appears Safe for Parkinson’s
In two Phase 1 trials, DNL201 reduced LRRK2 kinase activity in blood mononuclear cells. The inhibitor reached the same level in CSF as in blood. There were no serious side effects.
Amyloid Alone—Any Amyloid—Raises P-Tau in Mice
Cerebrospinal fluid p-tau217 and -181 rose in tandem with amyloid deposition in the brain, regardless of whether the plaques contained Aβ or amyloid formed by a different protein.
Double Spiral Sets TDP-43 Apart from Other Amyloids
Cryo-EM revealed that TDP-43 protofilaments from people with ALS/FTD formed the same structure, with a core of stacked double spirals. It is wildly different from that of TDP-43 filaments made in vitro, and from those of other amyloids.
Scientists Re-Analyze Aduhelm Data, Try to Parse Who Benefits
At AD/PD, some speakers sought to bolster the argument that amyloid removal slows cognitive decline, while others identified what type of patient is most likely to benefit.
Rare Variants Net New Alzheimer’s Gene, Links Between AD and CAA
Rare AD risk variants cluster within TREM2, SORL1, and the newcomer EXOC3L4. Rare mutations in ABCA7 associate with cerebral amyloid angiopathy.
A New PET Tracer Could Track Cholesterol Clearance from the Brain
18F-Cholestify binds to the enzyme that generates 24-hydroxycholesterol, which readily clears the blood-brain barrier.
Ubiquitin Peptidase Linked to Increased Tau Pathology in Women
USP11 spurs tau acetylation and aggregation. In women, one copy escapes X-inactivation.
“Numbing" Neurons Temper Tau in Mice
Without the trafficking protein Numb, tau accumulated in retinal ganglion cells and motor neurons, accelerating hind limb paralysis.
Cornucopia: LOADs of New Mouse Models Available
Scientists now have more options to model late-onset Alzheimer’s disease. APOE, TREM2, and gene combinations better mimic LOAD than do models of familial AD.
Bassoon Heralds Spread of Toxic Tau
Knocking down the synaptic scaffolding protein in mice eased neurofibrillary tangles, gliosis, and neurodegeneration.
Rare Variants in Lipid Transporter Genes Increase Risk for Alzheimer’s Disease
Along with previously identified rare variants in TREM2, SORL1, and ABCA7, a massive exome sequencing effort identified variants in ATP8B4 and ABCA1.
Aduhelm Phase 3 Data: ARIA Is Common, Sometimes Serious
Among those on the high dose, 41 percent developed ARIA, 1 percent had serious symptoms, some had recurring ARIA. Impending CMS decision draws debate.
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